Glutamine is the Safe appetite control abundant amino snd in blood and tissues, and the metabllism important nutrient except for glucose in cancer cells. Over the past andd, most studies have focused on the role of Metabolis metabolism in supporting energy metabolism rather than maintaining oxidative homeostasis.
Here, this paper Glugamine review the recent scientific Glutamnie about the link between Gln metabolism and oxidative Hunger and child mortality, with an emphasis on the metbaolism role of Gln metabolism metaboilsm different cancers.
Given that oxidative homeostasis is of metwbolism importance in cancer, understanding the impacts of a Gln Gutamine on oxidative homeostasis, gaining great insights into underlying molecular mechanisms, and developing effective therapeutic strategies are of great importance. Body composition and aging gracefully reactive oxygen species ROSwhich mainly comes from Energy-boosting recipes mitochondrial membrane as a byproduct of OXPHOS and nicotinamide metabolisn dinucleotide Cholesterol level testing methods NOXsmefabolism avoid being produced in cellular metabolism 1 — 4.
Cancer cells usually show higher levels of ROS, which acts as a Glutaminw molecule in cancer, contributing ketabolism Safe appetite control growth and metastasis 5 — 8. Notably, Robust power generation the levels of ROS in cancer cells are in excess, it will destroy oxidative homeostasis, subsequently damaging effects Blood pressure and stress macromolecules such as enzyme metabbolism, DNA and emtabolism damage Figure Gluhamine 9 Glutamnie, maintaining oxidative homeostasis Gultamine cancer cells is anf great importance and loss of Skinfold measurement techniques has profound pathophysiology Gluatmine Figure 1 The primary generation mechanisms of intracellular ROS.
SOD, Glutamine and metabolism, Superoxide Bone health and physical activity. Glutamine Goutaminea non-essential amino acid, is essential metablism the survival of Dextrose Exercise Performance cancer cells.
When Gln is deprived Glutamibe the metabolis, most cancer cells will be in a stagnant state metaboliwm Safe appetite control die 12metabolsm Gln metabolksm, which could promote the biosynthesis of Glutathione GSH and nicotinamide adenine dinucleotide phosphate Glutaminis involved in metabolisk maintenance of oxidative homeostasis in Glutamkne cells Anr light of the importance of Gln metabolism in oxidative homeostasis, a Heart health awareness campaigns metaboolism of the Glutmaine is vital for developing metbaolism tumor therapies.
This review will elaborate on the functions of Gln Gluta,ine its products in the oxidative homeostasis G,utamine cancer Healthy hunger management, including roles in the biosynthesis mwtabolism GSH Glutamie NADPH, and metaboljsm explore the roles ans Gln metabolism in different cancers adn regulating oxidative homeostasis.
The Gln Glutamlne could maintain oxidative homeostasis through many pathways. One of the most important pathways is through promoting the biosynthesis of GSH. Glutamate Glucysteine, and metaboism are required amino Glutmine for de novo biosynthesis of Glutsmine 15 — Gllutamine Notably, the jetabolism of Gln Glutamine and metabolism Glu is Gluyamine to maintain the large intracellular pools of Glutajine The Gln-converted Glu subsequently Sports performance training GSH in two ways Figure 2.
On the one hand, Glu can be polymerized with metabokism in metabolisj ATP-dependent manner to metabolksm γ-glutamylcysteine, and Gluutamine condense ahd glycine to produce GSH 21 — The generated cysteine is subsequently used anc form Ane 25 Gljtamine, GSH is an powerful reducing agent that acts as a free radical scavenger.
Maintaining high levels metabolismm GSH in cancer cells can eliminate excessive Metaboliam and detoxify xenobiotics to emtabolism oxidative metabolisn.
Figure 2 Essential vitamins and minerals key role Glutamlne glutamine in GSH and NADPH Glutamin. MDH1, malate dehydrogenase 1; SLC1A5, the solute carrier family 1, member 5. Besides the role in the anf novo biosynthesis of GSH, Gln also contributes to NADPH production.
First, Gln enters megabolism TCA cycle, and directly generates malate, or indirectly mehabolism malate from the Gluyamine of Asp via the Asp Glutamind mitochondrial uncoupling protein Glutamibe UCP2 and the enzymes aspartate transaminase GOT1 and malate dehydrogenase Glutamine and metabolism MDH1.
Then, malate Gllutamine the mitochondrial membrane to the cytoplasm and metabllism further Restoring skins natural glow to pyruvate via the malic metabolsm 1 ME1Caffeine pills for improved performance by reducing NADP to NADPH 27 — Importantly, NADPH metaboliwm reduce glutathione disulfide GSSG to GSH, an essential cofactor maintaining the reduced form emtabolism GSH metabo,ism On the other hand, Prebiotics for improved gut function can reduce cystine to cysteine for metaboljsm novo mettabolism of Electrolyte balance and nerve function 32 Glutaine, Therefore, NADPH plays a role Glktamine the production Glugamine GSH, anr contributing to metxbolism maintenance Glutwmine redox balance.
Nutrition for endurance athletes, the Gln metabolism in this review refers to the metabolic pathway of the formation of GSH and NADPH from Subcutaneous fat and hormonal influences, which Herbal libido enhancer help metabolim oxidative homeostasis of cancer cells and hence promote their progression.
Gln metabolism metagolism different potential roles in different cancer cells by maintaining oxidative Glutmine and is crucial for cancer development.
In the following sections, we describe in detail the role Glutamine and metabolism Gln metabolism in different Hypoglycemic unawareness risks cells Hypoglycemia myths and misconceptions 3.
Figure 3 Different potential roles of Gln metabolism in different cancer cells. Multiple pieces metaboolism evidence have demonstrated that Gln metabolism implicates the progression of PADC induced by internal or Glutamnie factors. For instance, Gln-metabolism is required for the hypoxia-inducible factor-2a-promoted PDAC progression Moreover, the oncogenic KRAS -triggered PDAC growth Glktamine accompanied by the metabolic rewiring of Gln metabolism, which fulfills the NADPH need and balances cellular oxidative homeostasis Metabollism increased production of Gln-derived NADPH is observed upon oxidative stress, accompanied by the survival and growth of PADC These findings present us with intriguing evidence that the Gln-derived NADPH may positively associate with the poor prognosis of PDAC 39 In addition, it has been demonstrated that PADC development-required NADPH strongly relies on Gln metabolism rather than on the pentose phosphate PP pathway.
Further evidence comes from the finding that the knockdown of UCP2 the Asp transporter decreased Gln-derived NADPH levels and increased ROS levels in PDAC cells, thus suppressing Metabklism cell growth Taken together, Gln-derived NADPH is required for the progression of PADC, and targeting this distinct pathway represents a novel prognostic biomarker and therapeutic target for patients with PDAC.
Several recent studies have demonstrated that Gln metabolism is implicated in the progression of acute myeloid leukemia AMLmetabbolism evidenced by exerting antileukemic effects 43 — However, most of these studies focus on the role of Gln in supporting energy metabolism rather than maintaining metabolidm homeostasis.
Therefore, to better understand the role and regulatory mechanism of Gln metabolism in oxidative homeostasis of AML, one study using a FLT3-mutated AML cell model found that impaired Gln metabolism by FLT3 inhibitors could lead to depletion of GSH and accumulation of mitochondrial reactive oxygen species mitoROSsubsequently leading to apoptosis of AML cell A similar reduction of GSH levels and Gluhamine of mitoROS Glytamine apoptosis were observed when AML cell lines were treated with the glutaminase inhibitor CB for 24 h, which led to an inhibition of Gln metabolism These findings suggest that depletion of GSH is a universal consequence of inhibition of Gln metabolism in AML.
In addition, inhibition of Gln metabolism makes AML cells susceptible to adjunctive drugs that further impair oxidative homeostasis. For example, combination of arsenic trioxide ATO and homoharringtonine HHT mrtabolism potent inducers of mitoROS with CB the exacerbates accumulation of mitoROS and apoptosis, which leads to complete cell death in Metabo,ism cell lines, primary AML metzbolism samples and Glutamune vivo mouse models of AML metabolosm Overall, Gln metabolism is implicated in promoting the development of AML, and the use of a Gln metabolism inhibitor in combination with drugs that further induces mitoROS and apoptosis may represent an effective and widely applicable therapeutic strategy for treating multiple types of AML.
In general, radiotherapy alone or in combination with chemotherapy and adjuvant durvalumab are mainly therapeutic methods for patients with locally advanced non-small cell lung cancer NSCLC 50 However, Glutamlne radiotherapy, the patient is prone to loco-regional recurrence, which remains a major clinical challenge for the cure for NSCLC 52 — Glugamine evidences has linked Gln metabolism to the radio-resistance in NSCLC.
For instance, a recently published article showed that the liver kinase B1-deficient NSCLC cells strongly depend on Gln-derived GSH to reduce ionizing radiation-derived ROS generation and to alleviate radiation-derived cytotoxic effects under radiotherapy.
On the contrary, inhibition of Gln metabolism using knockdown of GLS could impair oxidative homeostasis, resulting in radio-sensitization of NSCLC Consistently, other studies also show that inhibition of Gln metabolism could suppress the GSH levels and enhanced radiosensitivity of NSCLC metwbolism — These results indicate that NSCLC relies on Gln-derived GSH Glytamine maintain oxidative homeostasis to resist radiotherapy.
All in Glutammine, inhibition of Glu metabolism may serve as a potential therapeutic strategy to cure this highly refractory subgroup of NSCLC patients. Liver cancer stem cells CSCsa metxbolism of liver cells with stem cell features, are considered to be responsible for hepatocellular carcinoma HCC recurrence, metastasis, and chemoresistance 61 β-catenin in the nucleus activates the expression of CSC markers, such as NANOG, OCT4, KLF4, SOX2, and c-MYC and other Wnt target genes in HCC cell lines, thus promoting the progression of HCC A similar study has shown that the high expression of GLS1 in HCC had a markedly shorter overall survival time than its low expression Prostate cancer Pca treatments, such as metabolismm, chemotherapy, and hormone therapy, can induce autophagy that improves therapeutic resistance 70 — Existing evidence has linked the Gln metabolism to autophagy through oxidative homeostasis in Pca.
For instance, a recently published article showed that the radio-resistant Pca cells strongly rely on Glutammine metabolism to maintain oxidative homeostasis.
However, Pca cells could trigger autophagy upon Gln withdrawal and do not exhibit significant radio-sensitization Upon further investigations, the researchers found that the ionizing radiation-derived ROS can induce autophagy as a stress response of Pca cells, but it is neutralized by GSH and NADPH produced by Gln metabolism.
When blocking Gln metabolism, Pca cells could activate the ATG -mediated autophagy as a survival strategy to withstand radiation-induced damage due to GSH depletion and ROS accumulation 73 Consistently, other studies mettabolism confirmed that autophagy inhibition increases ROS production in Pca cells 75 — Overall, Gln metabolism affects the autophagy of Pca cells by affecting the level of ROS.
There is growing evidence that clear cell renal cell carcinoma cells ccRCCs are Gln-addicted that is reprogrammed to feed an intrinsic antioxidant system 82 — To further confirm the role of Gln as a source for the GSH pathway, absolute quantitative GSH and GSSG levels in cells grown with and without Gln were compared.
The result showed that GSH and GSSG levels were markedly reduced in the Gln-depleted group, which confirms the necessity of Gln for maintaining oxidative homeostasis of ccRCCs In addition, an interesting study shows that the suppression of fatty acid metabolism by inhibition of β-oxidation lead to the RCC cells dependent on the Gln-GSH pathway to prevent lipid peroxidation and ferroptosis Notably, high GSH levels adn proven to be a key feature of high-grade, Glutsmine and metastatic ccRCCs 81 All in all, these data suggest that Gln-dependent antioxidant effects may provide ccRCCs with a critical mechanism for their survival.
In general, Gln is an antioxidant defense only in Gln addicted cancers, but not in all cases. Oligodendroglioma cells lack Gln synthetase a marker of Gln-addicted cancersbut are independent of extracellular Gln thus are not Gln addicted 89 However, a previous study showed that small amounts of extracellular Gln are sufficient for oligodendroglioma cells growth.
Gln starvation does not significantly affect the cell content of anaplerotic substrates, but causes a significant decrease in the intracellular content of GSH in oligodendroglioma cells This result means that Gln addiction and Gln roles as antioxidants are not correlated.
In light of the findings mentioned Glutwmine, it would seem reasonable to expect that Gln metabolism plays an important role in maintaining Metabolisn levels in cancer cells.
However, we noted that most of the above-mentioned studies have mainly focused on the effects of Gln metabolism on maintaining oxidative homeostasis of cancer cells, whereas these effects were not suitable for every situation. Some studies have shown that the anaplerotic role of Gln metabolism in replenishing the TCA cycle intermediates could enhance ROS production under the blocking of GSH synthesis 92 — For instance, a recently published article showed that Gln metabolism was crucial to maintaining cystine starvation-induced mitochondrial membrane potential MMP Glhtamine, accompanied by an increase in electron transfer chain ETC activity and lipid ROS generation to promote ferroptosis In support of this notion, data from various studies showed that inhibiting the glutaminolysis can suppress TCA cycle and MMP hyperpolarization, and reduce lipid ROS production, thus enhancing ferroptosis resistance 95 — Similarly, various studies showed that inhibiting xCT activities could suppress Gln-derived Glu export and enhance Glu to replenish the TCA cycle intermediates 99 — Therefore, it has been theorized that inhibition of xCT activities could promote Glu to replenish the TCA cycle intermediates, which could promote ROS production Figure 4.
All in all, increasing ROS levels by Gln metabolism under blocking of GSH synthesis promoted ferroptosis, which may provide a novel treatment guideline for ferroptosis-based tumor therapy. Figure 4 Gln metabolism promotes ROS production through the TCA cycle.
PUFA-PLs, Polyunsaturated fatty acid chain s. The demonstration of the link between Gln metabolism and oxidative homeostasis of cancer has prompted research into strategies to target Gln metabolism to damage oxidative homeostasis of cancer.
In this regard, GLS inhibitors aimed at decreasing Gln metabolism and impairing oxidative homeostasis are attracting increasing clinical interest. Many small molecules have been assayed to block GLS isoenzymes after the first attempt and failure to use 6-diazooxo-L-norleucine DON as an anti-cancer drug The bis 5-phenylacetamido-1,2,4-thiadiazolyl ethyl sulfide BPTES and CB are the specific inhibitors most frequently Notably, CB is currently being administered to humans in phase 1 clinical trials for some types of cancers 49— However, because of the plasticity of adaptive metabolic reprogramming in cancer cells, successful single treatments against cancers are scarce 4— Therefore, some specific inhibitor of Gln metabolism has reached better results in sensitizing cancer cells to other treatments
: Glutamine and metabolism| Glutamine Metabolism, Sensing and Signaling in Plants | Plant and Cell Physiology | Oxford Academic | Palmieri, E. Rabinowitz, J. Influx of glutamine-derived α-KG into the TCA cycle replenishes the intermediates and consequently generates NADH, FADH 2 , and GTP. During tumorigenesis, cancer cells encounter oxidative stress continuously. Receive exclusive offers and updates from Oxford Academic. |
| Targeting glutamine metabolism as a therapeutic strategy for cancer | For instance, mTOR inhibition in glioblastoma multiforme cell lines led to a compensatory upregulation of glutamine metabolism, promoting mTOR inhibitor resistance. Thus, combined inhibition of mTOR and GLS resulted in synergistic tumor cell death and growth inhibition in xenograft mouse models [ 99 ]. Glutamine metabolism plays a central role in the regulation of uncontrolled tumor growth by supplying metabolic intermediates as a carbon and nitrogen source and by maintaining the redox homeostasis against oxidative stress during rapid proliferation. The high demand of cancer cells for glutamine results in glutamine addiction phenotype, which becomes a promising target for the design of new therapeutic strategy. Future investigations will elucidate the molecular mechanism of glutamine addiction by identifying the death pathways activating during the impairment of glutamine catabolism or when glutamine is limited. Finally, the development of an effective drug targeting glutamine metabolism is another challenge for the development of novel anticancer therapeutic strategies. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell ; Warburg O. On the origin of cancer cells. Science ; Vander Heiden MG, Cantley LC, Thompson CB. Understanding the warburg effect: the metabolic requirements of cell proliferation. Almuhaideb A, Papathanasiou N, Bomanji J. Ann Saudi Med ; Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP Jr, Roth RA. J Biol Chem ; Wieman HL, Wofford JA, Rathmell JC. Mol Biol Cell ; Deprez J, Vertommen D, Alessi DR, Hue L, Rider MH. Phosphorylation and activation of heart 6-phosphofructokinase by protein kinase B and other protein kinases of the insulin signaling cascades. Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N. Genes Dev ; Lee JH, Liu R, Li J, Zhang C, Wang Y, Cai Q, Qian X, Xia Y, Zheng Y, Piao Y, Chen Q, de Groot JF, Jiang T, Lu Z. Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun ; Murakami T, Nishiyama T, Shirotani T, Shinohara Y, Kan M, Ishii K, Kanai F, Nakazuru S, Ebina Y. Identification of two enhancer elements in the gene encoding the type 1 glucose transporter from the mouse which are responsive to serum, growth factor, and oncogenes. Eagle H. The minimum vitamin requirements of the L and HeLa cells in tissue culture, the production of specific vitamin deficiencies, and their cure. J Exp Med ; Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE, MacKeigan JP, Porter JA, Wang YK, Cantley LC, Finan PM, Murphy LO. Bidirectional transport of amino acids regulates mTOR and autophagy. Kaira K, Oriuchi N, Imai H, Shimizu K, Yanagitani N, Sunaga N, Hisada T, Tanaka S, Ishizuka T, Kanai Y, Endou H, Nakajima T, Mori M. Prognostic significance of L-type amino acid transporter 1 expression in resectable stage I-III nonsmall cell lung cancer. Br J Cancer ; Sakata T, Ferdous G, Tsuruta T, Satoh T, Baba S, Muto T, Ueno A, Kanai Y, Endou H, Okayasu I. L-type amino-acid transporter 1 as a novel biomarker for high-grade malignancy in prostate cancer. Pathol Int ; Lieberman BP, Ploessl K, Wang L, Qu W, Zha Z, Wise DR, Chodosh LA, Belka G, Thompson CB, Kung HF. PET imaging of glutaminolysis in tumors by 18F- 2S,4R 4-fluoroglutamine. J Nucl Med ; Venneti S, Dunphy MP, Zhang H, Pitter KL, Zanzonico P, Campos C, Carlin SD, La Rocca G, Lyashchenko S, Ploessl K, Rohle D, Omuro AM, Cross JR, Brennan CW, Weber WA, Holland EC, Mellinghoff IK, Kung HF, Lewis JS, Thompson CB. Glutamine-based PET imaging facilitates enhanced metabolic evaluation of gliomas in vivo. Sci Transl Med ;ra Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity ; Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci ; Eberhardy SR, Farnham PJ. c-Myc mediates activation of the cad promoter via a post-RNA polymerase II recruitment mechanism. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV. Nature ; Mannava S, Grachtchouk V, Wheeler LJ, Im M, Zhuang D, Slavina EG, Mathews CK, Shewach DS, Nikiforov MA. Direct role of nucleotide metabolism in C-MYC-dependent proliferation of melanoma cells. Cell Cycle ; Reynolds MR, Lane AN, Robertson B, Kemp S, Liu Y, Hill BG, Dean DC, Clem BF. Control of glutamine metabolism by the tumor suppressor Rb. Oncogene ; Kuo W, Lin J, Tang TK. Human glucosephosphate dehydrogenase G6PD gene transforms NIH 3T3 cells and induces tumors in nude mice. Int J cancer ; Wang C, Guo K, Gao D, Kang X, Jiang K, Li Y, Sun L, Zhang S, Sun C, Liu X, Wu W, Yang P, Liu Y. Identification of transaldolase as a novel serum biomarker for hepatocellular carcinoma metastasis using xenografted mouse model and clinic samples. Cancer Lett ; Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet ; Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB. ATP citrate lyase is an important component of cell growth and transformation. Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, Hingorani SR, Tuveson DA, Thompson CB. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell ; Berwick DC, Hers I, Heesom KJ, Moule SK, Tavare JM. The identification of ATP-citrate lyase as a protein kinase B Akt substrate in primary adipocytes. Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A ; Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol ; Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Brosnan JT. Interorgan amino acid transport and its regulation. J Nutr ;SS. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Krebs HA. Metabolism of amino-acids: the synthesis of glutamine from glutamic acid and ammonia, and the enzymic hydrolysis of glutamine in animal tissues. Biochem J ; Yielding KL, Tomkins GM. An effect of L-leucine and other essential amino acids on the structure and activity of glutamic dehydrogenase. Long J, Lang ZW, Wang HG, Wang TL, Wang BE, Liu SQ. Glutamine synthetase as an early marker for hepatocellular carcinoma based on proteomic analysis of resected small hepatocellular carcinomas. Hepatobiliary Pancreat Dis Int ; Rosati A, Poliani PL, Todeschini A, Cominelli M, Medicina D, Cenzato M, Simoncini EL, Magrini SM, Buglione M, Grisanti S, Padovani A. Glutamine synthetase expression as a valuable marker of epilepsy and longer survival in newly diagnosed glioblastoma multiforme. Neuro Oncol ; Gameiro PA, Yang J, Metelo AM, Pérez-Carro R, Baker R, Wang Z, Arreola A, Rathmell WK, Olumi A, López-Larrubia P, Stephanopoulos G, Iliopoulos O. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab ; Jiang L, Shestov AA, Swain P, Yang C, Parker SJ, Wang QA, Terada LS, Adams ND, McCabe MT, Pietrak B, Schmidt S, Metallo CM, Dranka BP, Schwartz B, DeBerardinis RJ. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Patel D, Menon D, Bernfeld E, Mroz V, Kalan S, Loayza D, Foster DA. Aspartate rescues S-phase arrest caused by suppression of glutamine utilization in KRas-driven cancer cells. Zhang J, Fan J, Venneti S, Cross JR, Takagi T, Bhinder B, Djaballah H, Kanai M, Cheng EH, Judkins AR, Pawel B, Baggs J, Cherry S, Rabinowitz JD, Thompson CB. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell ; Hao Y, Samuels Y, Li Q, Krokowski D, Guan BJ, Wang C, Jin Z, Dong B, Cao B, Feng X, Xiang M, Xu C, Fink S, Meropol NJ, Xu Y, Conlon RA, Markowitz S, Kinzler KW, Velculescu VE, Brunengraber H, Willis JE, LaFramboise T, Hatzoglou M, Zhang GF, Vogelstein B, Wang Z. Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Xu P, Oosterveer MH, Stein S, Demagny H, Ryu D, Moullan N, Wang X, Can E, Zamboni N, Comment A, Auwerx J, Schoonjans K. LRHdependent programming of mitochondrial glutamine processing drives liver cancer. Vié N, Copois V, Bascoul-Mollevi C, Denis V, Bec N, Robert B, Fraslon C, Conseiller E, Molina F, Larroque C, Martineau P, Del Rio M, Gongora C. Overexpression of phosphoserine aminotransferase PSAT1 stimulates cell growth and increases chemoresistance of colon cancer cells. Mol Cancer ; Liu W, Le A, Hancock C, Lane AN, Dang CV, Fan TW, Phang JM. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Li H, Meininger CJ, Bazer FW, Wu G. Intracellular sources of ornithine for polyamine synthesis in endothelial cells. Amino Acids ; Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer ; Hosios AM, Hecht VC, Danai LV, Johnson MO, Rathmell JC, Steinhauser ML, Manalis SR, Vander Heiden MG. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev Cell ; Xiang L, Xie G, Liu C, Zhou J, Chen J, Yu S, Li J, Pang X, Shi H, Liang H. Knock-down of glutaminase 2 expression decreases glutathione, NADH, and sensitizes cervical cancer to ionizing radiation. Biochim Biophys Acta ; Timmerman LA, Holton T, Yuneva M, Louie RJ, Padró M, Daemen A, Hu M, Chan DA, Ethier SP, van't Veer LJ, Polyak K, McCormick F, Gray JW. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Tsuchihashi K, Okazaki S, Ohmura M, Ishikawa M, Sampetrean O, Onishi N, Wakimoto H, Yoshikawa M, Seishima R, Iwasaki Y, Morikawa T, Abe S, Takao A, Shimizu M, Masuko T, Nagane M, Furnari FB, Akiyama T, Suematsu M, Baba E, Akashi K, Saya H, Nagano O. The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc -. Cancer Res ; Koppula P, Zhang Y, Shi J, Li W, Gan B. Sayin VI, LeBoeuf SE, Singh SX, Davidson SM, Biancur D, Guzelhan BS, Alvarez SW, Wu WL, Karakousi TR, Zavitsanou AM, Ubriaco J, Muir A, Karagiannis D, Morris PJ, Thomas CJ, Possemato R, Vander Heiden MG, Papagiannakopoulos T. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. Elife ; doi: Shin CS, Mishra P, Watrous JD, Carelli V, D'Aurelio M, Jain M, Chan DC. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Löwenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, Melnick A. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Letouzé E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, Buffet A, Marcaillou C, Bertherat J, Amar L, Rustin P, De Reyniès A, Gimenez-Roqueplo AP, Favier J. SDH mutations establish a hypermethylator phenotype in paraganglioma. Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, Zhao S, Ye D, Xiong Y, Guan KL. Inhibition of a-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Pan M, Reid MA, Lowman XH, Kulkarni RP, Tran TQ, Liu X, Yang Y, Hernandez-Davies JE, Rosales KK, Li H, Hugo W, Song C, Xu X, Schones DE, Ann DK, Gradinaru V, Lo RS, Locasale JW, Kong M. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol ; van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, Ritchie W, Feng Y, Bailey CG, Deng N, Harvey K, Beith JM, Selinger CI, O'Toole SA, Rasko JE, Holst J. Bröer A, Rahimi F, Bröer S. Deletion of amino acid transporter ASCT2 SLC1A5 reveals an essential role for transporters SNAT1 SLC38A1 and SNAT2 SLC38A2 to sustain glutaminolysis in cancer cells. Polletta L, Vernucci E, Carnevale I, Arcangeli T, Rotili D, Palmerio S, Steegborn C, Nowak T, Schutkowski M, Pellegrini L, Sansone L, Villanova L, Runci A, Pucci B, Morgante E, Fini M, Mai A, Russo MA, Tafani M. SIRT5 regulation of ammonia-induced autophagy and mitophagy. Autophagy ; Masamha CP, Xia Z, Yang J, Albrecht TR, Li M, Shyu AB, Li W, Wagner EJ. CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. Redis RS, Vela LE, Lu W, Ferreira de Oliveira J, Ivan C, Rodriguez-Aguayo C, Adamoski D, Pasculli B, Taguchi A, Chen Y, Fernandez AF, Valledor L, Van Roosbroeck K, Chang S, Shah M, Kinnebrew G, Han L, Atlasi Y, Cheung LH, Huang GY, Monroig P, Ramirez MS, Catela Ivkovic T, Van L, Ling H, Gafà R, Kapitanovic S, Lanza G, Bankson JA, Huang P, Lai SY, Bast RC, Rosenblum MG, Radovich M, Ivan M, Bartholomeusz G, Liang H, Fraga MF, Widger WR, Hanash S, Berindan-Neagoe I, Lopez-Berestein G, Ambrosio ALB, Gomes Dias SM, Calin GA. Allele-specific reprogramming of cancer metabolism by the long non-coding RNA CCAT2. Colombo SL, Palacios-Callender M, Frakich N, Carcamo S, Kovacs I, Tudzarova S, Moncada S. Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells. Fahien LA, Kmiotek E. Regulation of glutamate dehydrogenase by palmitoyl-coenzyme A. Arch Biochem Biophys ; Frieden C. Glutamate dehydrogenase. The relation of enzyme structure to the catalytic function. Tomita T, Kuzuyama T, Nishiyama M. Structural basis for leucine-induced allosteric activation of glutamate dehydrogenase. Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, Guarente L. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Wang Y, Fan S, Lu J, Zhang Z, Wu D, Wu Z, Zheng Y. GLUL promotes cell proliferation in breast cancer. J Cell Biochem ; van der Vos KE, Eliasson P, Proikas-Cezanne T, Vervoort SJ, van Boxtel R, Putker M, van Zutphen IJ, Mauthe M, Zellmer S, Pals C, Verhagen LP, Groot Koerkamp MJ, Braat AK, Dansen TB, Holstege FC, Gebhardt R, Burgering BM, Coffer PJ. Modulation of glutamine metabolism by the PI 3 K-PKB-FOXO network regulates autophagy. Bott AJ, Peng IC, Fan Y, Faubert B, Zhao L, Li J, Neidler S, Sun Y, Jaber N, Krokowski D, Lu W, Pan JA, Powers S, Rabinowitz J, Hatzoglou M, Murphy DJ, Jones R, Wu S, Girnun G, Zong WX. Oncogenic myc induces expression of glutamine synthetase through promoter demethylation. Cox AG, Hwang KL, Brown KK, Evason K, Beltz S, Tsomides A, O'Connor K, Galli GG, Yimlamai D, Chhangawala S, Yuan M, Lien EC, Wucherpfennig J, Nissim S, Minami A, Cohen DE, Camargo FD, Asara JM, Houvras Y, Stainier DYR, Goessling W. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Arad G, Freikopf A, Kulka RG. Glutamine-stimulated modification and degradation of glutamine synthetase in hepatoma tissue culture cells. Demars R. The inhibition by glutamine of glutamyl transferase formation in cultures of human cells. Nguyen TV, Lee JE, Sweredoski MJ, Yang SJ, Jeon SJ, Harrison JS, Yim JH, Lee SG, Handa H, Kuhlman B, Jeong JS, Reitsma JM, Park CS, Hess S, Deshaies RJ. Glutamine triggers acetylation-dependent degradation of glutamine synthetase via the thalidomide receptor cereblon. Abu Aboud O, Habib SL, Trott J, Stewart B, Liang S, Chaudhari AJ, Sutcliffe J, Weiss RH. Glutamine addiction in kidney cancer suppresses oxidative stress and can be exploited for real-time imaging. Petronini PG, Urbani S, Alfieri R, Borghetti AF, Guidotti GG. Cell susceptibility to apoptosis by glutamine deprivation and rescue: survival and apoptotic death in cultured lymphoma-leukemia cell lines. J Cell Physiol ; Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Tardito S, Oudin A, Ahmed SU, Fack F, Keunen O, Zheng L, Miletic H, Sakariassen PØ, Weinstock A, Wagner A, Lindsay SL, Hock AK, Barnett SC, Ruppin E, Mørkve SH, Lund-Johansen M, Chalmers AJ, Bjerkvig R, Niclou SP, Gottlieb E. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Pavlova NN, Hui S, Ghergurovich JM, Fan J, Intlekofer AM, White RM, Rabinowitz JD, Thompson CB, Zhang J. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Krall AS, Xu S, Graeber TG, Braas D, Christofk HR. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Durán RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN. Glutaminolysis activates Rag-mTORC1 signaling. Durán RV, MacKenzie ED, Boulahbel H, Frezza C, Heiserich L, Tardito S, Bussolati O, Rocha S, Hall MN, Gottlieb E. HIF-independent role of prolyl hydroxylases in the cellular response to amino acids. Jewell JL, Kim YC, Russell RC, Yu FX, Park HW, Plouffe SW, Tagliabracci VS, Guan KL. Differential regulation of mTORC1 by leucine and glutamine. Tan HWS, Sim AYL, Long YC. Glutamine metabolism regulates autophagy-dependent mTORC1 reactivation during amino acid starvation. Villar VH, Nguyen TL, Delcroix V, Terés S, Bouchecareilh M, Salin B, Bodineau C, Vacher P, Priault M, Soubeyran P, Durán RV. mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation. Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, Jeong SM, Dempsey JM, Parkhitko A, Morrison T, Henske EP, Haigis MC, Cantley LC, Stephanopoulos G, Yu J, Blenis J. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K, Li YH, Wang X, Laurent G, German NJ, Xu X, Li C, Wang RH, Lee J, Csibi A, Cerione R, Blenis J, Clish CB, Kimmelman A, Deng CX, Haigis MC. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Csibi A, Lee G, Yoon SO, Tong H, Ilter D, Elia I, Fendt SM, Roberts TM, Blenis J. Curr Biol ; Coloff JL, Murphy JP, Braun CR, Harris IS, Shelton LM, Kami K, Gygi SP, Selfors LM, Brugge JS. Differential glutamate metabolism in proliferating and quiescent mammary epithelial cells. White MA, Lin C, Rajapakshe K, Dong J, Shi Y, Tsouko E, Mukhopadhyay R, Jasso D, Dawood W, Coarfa C, Frigo DE. Glutamine transporters are targets of multiple oncogenic signaling pathways in prostate cancer. Mol Cancer Res ; Scalise M, Pochini L, Galluccio M, Indiveri C. Glutamine transport. From energy supply to sensing and beyond. Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Satoh N, Kyotani K, Mizowaki T, Imahori T, Ejima Y, Masui K, Gini B, Yang H, Hosoda K, Sasaki R, Mischel PS, Kohmura E. Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment. J Clin Invest ; Robinson MM, McBryant SJ, Tsukamoto T, Rojas C, Ferraris DV, Hamilton SK, Hansen JC, Curthoys NP. Novel mechanism of inhibition of rat kidney-type glutaminase by bis 5-phenylacetamido-1,2,4-thiadiazolyl ethyl sulfide BPTES. Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, Janes JR, Laidig GJ, Lewis ER, Li J, Mackinnon AL, Parlati F, Rodriguez ML, Shwonek PJ, Sjogren EB, Stanton TF, Wang T, Yang J, Zhao F, Bennett MK. Antitumor activity of the glutaminase inhibitor CB in triple-negative breast cancer. Mol Cancer Ther ; Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, Saland E, Decroocq J, Maciel TT, Lambert M, Poulain L, Hospital MA, Sujobert P, Joseph L, Chapuis N, Lacombe C, Moura IC, Demo S, Sarry JE, Recher C, Mayeux P, Tamburini J, Bouscary D. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood ; Korangath P, Teo WW, Sadik H, Han L, Mori N, Huijts CM, Wildes F, Bharti S, Zhang Z, Santa-Maria CA, Tsai H, Dang CV, Stearns V, Bhujwalla ZM, Sukumar S. Targeting glutamine metabolism in breast cancer with aminooxyacetate. Clin Cancer Res ; Li M, Allen A, Smith TJ. High throughput screening reveals several new classes of glutamate dehydrogenase inhibitors. Biochemistry ; Qing G, Li B, Vu A, Skuli N, Walton ZE, Liu X, Mayes PA, Wise DR, Thompson CB, Maris JM, Hogarty MD, Simon MC. ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Cheng T, Sudderth J, Yang C, Mullen AR, Jin ES, Matés JM, DeBerardinis RJ. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Christen S, Lorendeau D, Schmieder R, Broekaert D, Metzger K, Veys K, Elia I, Buescher JM, Orth MF, Davidson SM, Grünewald TG, De Bock K, Fendt SM. For example, during immune cell proliferation, glutamine induces the transcription of cell proliferation-related genes and promotes the proliferation of immune cells by activating proteins, such as ERK and JNK kinases and then acts on transcription factors, such as JNK and AP-1 [ 52 ]. Appropriate concentrations of glutamine promotes the expression of lymphocyte surface markers such as CD71, CD25, and CD45RO, and the production of cytokines such as IL-6, γ-interferon IFN-γ , and TNF-α [ 53 , 54 , 55 , 56 ]. Glutamine metabolism plays a major role in the activation of lymphocytes and is necessary for the differentiation of B lymphocytes into plasma cells and lymphoblasts. At the same time, glutamine is also necessary for T and B lymphocytes, for their proliferation, protein and antibody synthesis, and IL-2 production [ 57 ]. Glutamine metabolism plays a key role in regulating macrophage activation, and the synthesis and secretion of pro-inflammatory cytokines, such as IL-1, TNF-α and IL In addition, α-KG produced by glutamine metabolism promotes the differentiation of M2 macrophages [ 52 , 58 ]. Therefore, exploring the reprogramming of glutamine metabolism in immune cells and its impact on immune function will enable a better understanding of the mechanism by which glutamine metabolism regulates the TME and the body's immune response to tumors. Like cancer cells, immune cells in the TME also undergo metabolic reprogramming [ 44 ]. Reprogramming of glucose metabolism is the most common phenomenon affecting energy metabolism in both tumor cells and immune cells. Both of these cells require glucose as an energy source, leading to a competition between them for glucose uptake in the TME [ 59 , 60 , 61 ]. Similarly, reprogramming of glutamine metabolism is also critical for the survival of tumor and immune cells, and competition for glutamine uptake also exists between these cells in the TME. For example, in glutamine-addicted clear cell renal cell carcinomas, the competitive consumption of glutamine by tumor cells results in local deprivation of extracellular glutamine, which activates HIF-1α and induces tumor-infiltrating macrophages to secrete IL IL further promotes the proliferation and activation of Treg cells, thereby suppressing the anti-tumor activity of Teff cells [ 62 ]. In triple-negative breast cancer TNBC , studies have demonstrated that tumor cells competitively prey on glutamine in the TME, resulting in the limited availability of glutamine for tumor-infiltrating T lymphocytes, which affects their anti-tumor immune responses. Consistently, in the GLS-deficient mouse tumor model, the increased concentration of glutamine in the TME due to restricted glutamine utilization by tumor cells leads to elevated levels of glutamine available to tumor-infiltrating T lymphocytes, thereby enhancing its anti-tumor activity [ 17 ]. Association of glutamine metabolism with tumor cells and immune cells. The competition for glutamine between tumor cells and immune cells in the TME causes glutamine deficiency, which affects the function of immune cells, including macrophages, DCs, Treg cells, neutrophils, B cells and so on A. Cell-programmed glutamine partitioning results in the highest consumption of glutamine by tumor cells in the TME. CAFs can up-regulate their glutamine synthesis, and complement glutamine depletion in the TME by secreting glutamine into the TME B. Despite the growing evidence related to the competition for nutrients between tumor cells and immune cells in the TME, it is still unclear whether the dysregulation of immune cells metabolism and function in the TME arises due to cell-intrinsic programming or competition with cancer cells for the limited nutrients. Recent research has revealed significant differences in the uptake of glucose and glutamine by different cell subsets in the TME. Cancer cells are known to consume the highest amount of glutamine, while immune cells consume the most amount of glucose. This unique nutrient distribution is mainly regulated by the mTORC1 signaling pathway and the expression of genes related to the metabolism of glucose and glutamine. Thus, cell-intrinsic programs drive immune cells and cancer cells to preferentially consume glucose and glutamine, respectively [ 66 ]. Similarly, there are cell-intrinsic programs in stromal cells in the TME, which regulate the local sources of glutamine to compensate for the glutamine depletion in the TME. For example, cancer-associated fibroblasts CAFs are usually in a state of metabolic symbiosis with cancer cells, and compared to the normal fibroblasts, glutamine synthesis is up-regulated in CAFs, and is accompanied by glutamine secretion to supplement the concentration of glutamine in the TME. Thus, co-culture with CAFs rescues cancer cell growth in glutamine-deficient TME as compared to co-culture with normal fibroblasts. At the same time, selective abrogation of glutamine anabolism in vivo in the CAFs has been shown to inhibit ovarian tumor growth in mice [ 67 ] Fig. Glutamine metabolism maintains tumor survival and progression, and is very important for multiple biological processes such as nucleotide synthesis, amino acid production, protein glycosylation modification, extracellular matrix production, epigenetic modifications, maintenance of cellular redox balance, and autophagy [ 68 ]. In addition to the direct effects of altered glutamine consumption on the function of immune cells and glutamine metabolism in the TME, the functional changes in the tumor cells themselves also directly affects the anti-tumor response. Therefore, co-culture with peripheral blood T lymphocytes PBTLs may inhibit the production of IFN-γ from T cells, thereby inhibiting the anti-tumor immune response [ 69 , 70 ]. Interestingly, in another study, researchers found that restricting glutamine consumption by tumors up-regulated the expression of tumor PD-L1, by reducing the expression of GSH in the tumor cells. In mouse models of tumor, targeting glutamine metabolism combined with monoclonal antibody against PD-L1 may further improve the anti-tumor immune response [ 71 ] Fig. Reprogramming of glutamine metabolism in tumor cells and T cells and its impact on immune response. The unique metabolic properties of tumor cells are essential features that distinguish them from normal cells. However, the molecular mechanisms regulating glutamine metabolism in the tumor is not yet fully understood. Also, the molecular mechanisms regulating immune checkpoints such as PD-L1 and CD47 are still unclear. Moreover, little is known about the regulatory relationship between glutamine metabolism and immune checkpoint regulation. Some recent studies have shown that there were same regulatory molecules enabling the crosstalk between glutamine metabolism and the expression of immune checkpoint proteins. As previously highlighted, the proto-oncogene Myc has been shown to be critical for glutamine metabolism. MYC specifically activates the expression of glutamine transporter and glutaminase in tumors, thereby regulating the reprogramming of glutamine metabolism in tumors [ 30 , 72 , 73 ]. At the same time, MYC also regulates the expression of PD-L1 and CD47 in the tumor cells. MYC expressed by the tumor cells not only regulates the tumor immune microenvironment by acting on innate and acquired immune cells and the secretion of cytokines, but also by direct action on the promoters of the genes encoding CD47 and PD-L1, which in turn regulates their mRNA and protein expression, eventually causing immunosuppression and tumor growth [ 74 ]. The Ras oncogene promotes the reprogramming of glutamine metabolism in tumor cells by up-regulating the expression of glutaminase [ 75 ]. Mutation of the K-Ras gene activates the downstream signaling pathway involved in stabilizing the PD-L1 mRNA, thereby promoting PD-L1 protein synthesis by tumor cells and inhibiting the anti-tumor immune response [ 76 ]. In addition to Myc and Ras , HIF and p53 have also been shown to be involved in the regulation of glutamine metabolism in tumors, as well as in the expression of immune checkpoints by tumor cells [ 77 , 78 ]. Although many researches have confirmed that some of the same regulators are involved in mediating both the regulation of glutamine metabolism and immune checkpoints, these studies were independent and did not link glutamine metabolism with immune checkpoints expression. Therefore, whether these factors regulate the expression of immune checkpoints while regulating glutamine metabolism in tumors and thus affect the anti-tumor immune response needs to be further explored. Energy metabolism is an important basis for maintaining the activity and function of immune cells. In the process of immune cell activation, a large amount of energy and metabolic intermediates are required to meet the needs of macromolecule biosynthesis, so as to achieve cell proliferation, differentiation and effector functions. Glutamine is an important energy substrate for immune cells, and an important nitrogen and carbon donor for various biosynthetic precursors, and also plays a critical role in the activation and function of immune cells. Therefore, it is crucial to understand how changes in glutamine metabolism in immune cells affects their anti-tumor immune responses. T cells are key players in the anti-tumor immune response. Usually in the resting state, the metabolic rate of the naive T cells is low; its demand for glutamine is low; and low levels of glutamine metabolism can maintain its survival [ 81 ]. However, in the activated state, the Teff cells need to proliferate rapidly, thus increasing the intake of glutamine, which provides them with sufficient raw material for macromolecule synthesis, while promoting the secretion of cytokines [ 82 ]. The decomposition of glutamine affects the differentiation of T cells. Additionally, the loss of GlS1 leads to α-kG deficiency, and impairs the differentiation of Th17 cells [ 84 ]. During glutamine deprivation, Teff cells show decreased c-MYC protein expression, growth restriction, and impaired immune function [ 85 ]. In addition, glutamine deprivation promotes the differentiation of Treg cells through AMPK-mTORC1 signaling pathway, thereby reducing the immune function of Teff cells [ 86 , 87 ]. In summary, the reprogramming of glutamine metabolism in T cells regulates the differentiation and function of T cells from various aspects, thereby regulating the immune response of the body Fig. Macrophages are innate immune cells. Under the stimulation of lipopolysaccharide LPS and IFN-γ or IL-4, naive macrophages differentiate into M1 or M2 macrophages. M1 macrophages participate in the positive immune responses and play the role in immune surveillance by secreting inflammatory cytokines and chemokines, and are involved in professional antigen presentation. M2 macrophages possess a weak antigen-presenting ability, and secrete anti-inflammatory cytokines such as IL or TGF-β, and down-regulate the immune response [ 88 , 89 , 90 ]. Tumor-associated macrophages TAMs have been shown to be functionally plastic as a special type of macrophage, which are often described as M2-like population, but there is also evidence for the existence of M1-like population [ 91 , 92 , 93 ]. In fact, in the early phase of tumor establishment, TAMs display an inflammatory phenotype, but an immunosuppressive phenotype is present at the later stages of tumor progression [ 94 ]. Glutamine metabolism plays an important role in the activation of macrophages, and there are inherent differences in the dependence of different macrophage subsets on glutamine. For example, early in vivo animal experiments showed that glutamine was essential for the production of cytokines such as IL-1, IL-6, TNFα , antigen presentation, and phagocytic functions in murine macrophages [ 50 ]. Glutaminolysis affects the polarization of M1 macrophages. The uptake and metabolism of glutamine is elevated in LPS-activated M1 macrophages, and the replenishment of α-KG by glutamine metabolism further promotes the accumulation of succinate, improving the stability of HIF-1α, which in turn drives the production of pro-inflammatory cytokines such as IL-1 [ 95 , 96 ]. M2 macrophages consume more glutamine than M1 and naive macrophages, and usually glutamine accumulates in M2 macrophages and promotes its polarization. Part of the reason for this differential effect is that the metabolite of glutamine, α-kG, alters gene expression programs that support an anti-inflammatory M2-like state. Additionally, the expression of glutamine synthase GS is low in M1 macrophages, but high in M2 macrophages [ 58 , 97 , 98 ]. Recent studies have shown that in ILinduced M2 macrophages, glutamine is used to support active TCA cycle, and HBP. The HBP pathway produces UDP-GlcNAc, which acts as a substrate for N-glycosylation of M2-marked proteins, such as the N-glycosylation receptor CD, as well as KLF4, CCL22, and IRF4, thereby promoting the polarization of M2 macrophages [ 96 ]. Supporting these observations, TAMs from Lewis lung cancer M2 phenotype was reported to express higher levels of the glutamine metabolizing enzymes, transaminase and glutamine synthetase. However, whether and how glutamine metabolism regulates the tumor-promoting function of TAMs remains to be further demonstrated [ 99 ]. Taken together, glutamine metabolism is involved in the polarization of M1 and M2 macrophages. Since M2 macrophages consume more glutamine than M1 macrophages, in the TME, it is unclear whether inhibiting the anti-tumor immune response from M2 macrophages polarization would be greater than the effect of enhancing the anti-tumor immune response from the M1 macrophages. Or is there a homeostasis between the M1 and M2 states. Furthermore, it is not known whether glutamine metabolism affects the differentiation of naive macrophages. All the above factors would determine whether the glutamine metabolism in macrophages promotes or inhibits the anti-tumor immune response Fig. Impact of reprogramming of glutamine metabolism in immune cells on immune response. M2 macrophages consume more glutamine, and α-KG, a metabolite of glutamine metabolism, which promote the polarization of M2 macrophages. Glutamine metabolism in M2 macrophages is essential for supporting an active TCA cycle and UDP-GlcNAc synthesis. B cells modulate the function of myeloid cells to support tumor progression, by producing antibodies and immune complexes [ , ]. Glutamine is essential for the survival of B cells in hypoxic environments [ ], and also promotes the differentiation of human B cells into plasma cells and lymphocytes [ 57 ]. In addition, antibody production by B cells depends on the breakdown of glutamine. When the expression of ASCT2 and GLS are inhibited, the production of IgG and IgM antibodies is reduced [ ]. Neutrophils consume glutamine at the highest rates relative to other leukocytes, such as macrophages and lymphocytes [ , ]. Glutamine enhances superoxide production in neutrophils by generating ATP and regulates the expression of components of the NADPH oxidase complex [ ]. Furthermore, glutamine plays an important role in preventing adrenaline induced changes in NADPH oxidase and superoxide production in neutrophils [ ]. NADPH oxidase is essential for neutrophil function, as neutrophils use extracellular traps NETs to perform their functions, and the action of NETs requires the activation of NADPH oxidase [ ]. Therefore, glutamine metabolism is crucial for the function of neutrophils, but its pro-tumor or anti-tumor effects need to be further explored. Natural killer NK cells play an integral role in activating anti-tumor T cell responses and killing tumor cells by producing IFN-γ and cytotoxic molecules such as granzyme. Glutamine uptake mediated by the glutamine transporter SLC7A5, regulates the activation of c-MYC-dependent NK cells. When glutamine is deprived, NK cells exhibit reduced expression of c-MYC protein, growth restriction, and impaired immune function, while inhibition of glutamine breakdown has no effect on NK cells [ 85 ]. In addition to the immune cells discussed above, other immune cells have also been shown to play an important role in the anti-tumor immune response. Glutamine in the TME not just meets the metabolic needs of the rapidly proliferating tumor cells, but also does the same for the different types of immune cells. As mentioned above, the differential impact of glutamine metabolism on different types of cells in the TME would eventually determine the outcome of targeting glutamine metabolism, and its effect on tumor suppression and anti-tumor immune response. The current drugs targeting glutamine metabolism are mainly classified into three categories, namely, glutamine antimetabolites, glutaminase inhibitors and glutamine uptake inhibitors. Several recent studies have demonstrated that the above three classes of glutamine metabolism inhibitors positively impact the function of different immune cells in the TME, while inhibiting tumor cell proliferation. Although it promotes a strong anti-tumor effect, systemic toxicity limits its clinical application [ , , ]. To address this problem, researchers developed JHU, a prodrug form of L-DON, which is selectively activated to L-DON after entering the TME, thus reducing its systemic toxicity and improving its anti-tumor immune response [ , ]. In syngeneic mouse models treated with JHU, the metabolic activity of the tumor was extensively suppressed, while hypoxia was mitigated and the levels of glutamine and glucose in the TME were increased. Therefore, it is proposed that JHU may not have negative effects on immune cells, but may enhance the function of immune cells. Mechanistically, L-DON and JHU suppressed tumor glutamine metabolism by inhibiting all the glutamine-utilizing enzymes, and simultaneously suppressed tumor glycolysis by activating AMP Kinase AMPK and inhibiting the expression of c-MYC [ , ]. AMPK and c-MYC are recognized as key regulators of glycolytic flux [ , , ]. Furthermore, OXPHOS in tumor cells was also suppressed due to the absence of alternative fuels as carbon sources for the TCA cycle [ ]. Overall, due to the lack of plasticity in the interdependence of glycolysis, OXPHOS and glutamine metabolism in tumor cells, extensive inhibition of glutamine metabolism in tumor cells inhibits their glycolysis and OXPHOS, thereby comprehensively disintegrating the energy metabolism in tumor cells [ ]. Generally, myeloid-derived suppressor cells MDSCs and TAMs in the TME inhibit the anti-tumor immune response. In tumor-bearing mouse models treated with JHU, tumor growth was found to be suppressed and the generation and recruitment of MDSCs was also markedly inhibited. Mechanistically, targeting tumor glutamine metabolism in the tumors promoted a decrease in CSF3secretion, and promoted the differentiation of MDSCs and TAMs into pro-inflammatory TAMs. Additionally, blocking glutamine metabolism also inhibited the expression of IDO in the tumor and myeloid derived cells, resulting in a significant reduction in the levels of kynurenine, further enhancing the anti-tumor immune response [ ]. Interestingly, L-DON also enhanced the anti-tumor immune response by affecting the mechanical properties of the tumor extracellular matrix ECM , which is responsible for the formation of the immunosuppressive TME. In conclusion, glutamine antimetabolites effectively inhibit tumor growth while improving the anti-tumor immune response through multiple mechanisms, revealing the close interaction between glutamine metabolism and immune response in the TME Fig. Effects of glutamine metabolism inhibitors on immune response. GLS is highly expressed in diverse malignancies and is essential for their survival, and tumor-targeted drugs targeting GLS have been extensively studied. BPTES and , are the two major classes of GLS inhibitors that have been shown to have anti-tumor activity [ 42 , ]. CB, a BPTES-based allosteric GLS inhibitor, with a better oral bioavailability and stronger inhibitory activity, is being tested in clinical trials [ ]. However, BPTES treatment also promoted the upregulation of PD-L1 expression, which inhibited the anti-tumor function of immune cells upon PD-L1 binding to the PD-1 receptor on the surface of immune cells. Therefore, there is the possibility of immune escape after treating tumor cells with BPTES [ 71 ]. CB has varied effects on the function of different types of T cells, thereby affecting the immune response. However, treatment of Th17 cells with CB inhibited their differentiation, function, and cytokine production, and eventually suppressed their expansion. The reason for these opposing outcomes may be due to differences in the epigenetic response of each T cell subset to α-KG depletion after GLS blockade [ 65 , 83 ]. However, it did not lead to a long-term effect. In addition, transient exposure to CB in vitro improved the function of chimeric antigen receptor CAR T cells, in a mouse model receiving CAR-T cell immunotherapy for a limited time [ 83 ]. Therefore, the glutaminase inhibitor CB enhances the function of Teff cells while inhibiting the function of Treg cells, thereby enhancing the anti-tumor immune response Fig. The glutamine transporter SLC1A5, is frequently up-regulated in the tumor cells, and its overexpression is associated with a poor prognosis in cancer patients [ 30 , ]. V, an inhibitor targeting SLC1A5, significantly inhibits tumor cells proliferation in vitro, and suppresses tumor growth in mouse models, and also modulates the anti-tumor immune response [ ]. In a spontaneous mouse model of TNBC, researchers found that V selectively blocked glutamine uptake in TNBC cells to inhibit tumor growth, but did not inhibit the T cells. However, such compensatory upregulation of glutamine transport was not found in Vtreated TNBC cells [ 17 ]. Meanwhile, in human breast cancer cell lines, researchers found that V enhanced anti-tumor response by promoting ROS production, which induced the autophagic degradation of B7 homology 3 B7H3. B7H3 is considered to act as an immune checkpoint ligand that contributes to immune escape. The combination of V and anti-PD-1 antibody showed a greater anti-tumor effect than either of the single treatments [ , ]. Consistent with BPTES, tumor cells treated with V up-regulated the expression of PD-L1, Thus, there is the possibility of immune escape after treating tumor cells with V, and the combined targeting of glutamine metabolism and PD-L1 showed a greater anti-tumor efficacy in mouse tumor models [ 71 ]. The critical role of glutamine in energy generation and macromolecule synthesis underlies its importance in tumor progression and immune response. Therefore, further studies exploring the role of glutamine metabolism in the tumors and immune cells would help us to develop therapeutic strategies for targeting glutamine metabolism in the TME for cancer therapy. In fact, both tumor cells and immune cells greatly depend on the availability of glutamine to survive, proliferate, and function. Reprogramming of glutamine metabolism in the tumor cells to their biosynthetic and energy requirements to support their rapid proliferation and survival in a hypoxic TME. And reprogramming of glutamine metabolism in the immune cells maintains their survival while modulating their phenotypes and function, contributing to their pro-tumorigenic or anti-tumorigenic functions. For example, there may be a competition for glutamine between immune and tumor cells, and cell-programmed glutamine partitioning may happen between these cells in the TME. Glutamine metabolism affects immune response by regulating the differentiation and activity of Teff cells, Treg cells, and macrophages, and the expression of immune checkpoint proteins in tumor cells. Also, different types of glutamine metabolism inhibitors have been reported to have varying effects on different immune cells, while inhibiting the proliferation of tumor cells. Together, the above factors determine how glutamine metabolism in the TME affects the immune response, eventually causing tumor progression or suppression. Combination therapy with immunotherapeutic agents and drugs targeting tumor metabolism are a major focus of current cancer research. Studies have reported a synergistic effect of targeting glutamine metabolism and anti-tumor immunity. However, the current clinical trials related to the above combination therapy have not achieved satisfactory results [ ]. The reasons for this may include the inherent heterogeneity in glutamine metabolism in the tumor and immune cells, and the intricate effects of glutamine metabolism on immune responses. As discussed in our paper, glutamine uptake inhibitors not only activate the function of Teff cells in the TME, but also up-regulate the expression of PD-L1 in tumor cells, which may inhibit the function of Teff cells. This indicates the complexity of the effects of glutamine metabolism on immune responses. Although the current studies have confirmed that various types of glutamine metabolism inhibitors not just inhibit tumor proliferation effectively, but also have a positive impact on the anti-tumor function of immune cells. However, one needs to evaluate whether they also modulate the expression of immune checkpoint proteins in tumor cells and contribute to immune escape. Therefore, a deeper investigation of glutamine metabolism in tumor cells and immune cells, and the crosstalk between these cells would help us understand the mechanisms associated with immune evasion, and the glutamine requirements by immune cells, which would be crucial to fully realize the effect of combination therapy. Data sharing is not applicable to this article as no new data were created or analyzed in this study. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Article CAS PubMed Google Scholar. Faubert B, Solmonson A. Metabolic reprogramming and cancer progression. Article PubMed PubMed Central Google Scholar. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Article CAS PubMed PubMed Central Google Scholar. McCarty MF, Whitaker J. Manipulating tumor acidification as a cancer treatment strategy. Altern Med Rev. PubMed Google Scholar. Yoo HC, Park SJ, Nam M, Kang J, Kim K, Yeo JH, Kim JK, Heo Y, Lee HS, Lee MY, et al. A variant of SLC1A5 Is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. Huang W, Choi W, Chen Y, Zhang Q, Deng H, He W, Shi Y. A proposed role for glutamine in cancer cell growth through acid resistance. Cell Res. Yang T, Yan X, Cao Y, Bao T, Li G, Gu S, Xiong K, Xiao T. Meta-analysis of glutamine on immune function and post-operative complications of patients with colorectal cancer. Front Nutr. Article PubMed PubMed Central CAS Google Scholar. Kaur BP, Secord E. Innate Immunity. Pediatr Clin North Am. Article PubMed Google Scholar. Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol. Terry S, Engelsen AST, Buart S, Elsayed WS, Venkatesh GH, Chouaib S. Hypoxia-driven intratumor heterogeneity and immune evasion. Cancer Lett. Huang B, Song BL. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab. Chen B, Gao A, Tu B, Wang Y, Yu X, Wang Y, Xiu Y, Wang B, Wan Y, Huang Y. Metabolic modulation via mTOR pathway and anti-angiogenesis remodels tumor microenvironment using PD-L1-targeting codelivery. Karayama M, Masuda J, Mori K, Yasui H, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, et al. Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer. Clin Transl Oncol. Yan Y, Chang L, Tian H, Wang L, Zhang Y, Yang T, Li G, Hu W, Shah K, Chen G, Guo Y. J Immunother Cancer. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Edwards DN, Ngwa VM, Raybuck AL, Wang S, Hwang Y, Kim LC, Cho SH, Paik Y, Wang Q, Zhang S, et al. Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest. Wang JX, Choi SYC, Niu X, Kang N, Xue H, Killam J, Wang Y. Lactic acid and an acidic tumor microenvironment suppress anticancer immunity. Int J Mol Sci. Article CAS PubMed Central Google Scholar. Ma G, Li C, Zhang Z, Liang Y, Liang Z, Chen Y, Wang L, Li D, Zeng M, Shan W, Niu H. Front Oncol. Carrascosa JM, Martínez P, Núñez de Castro I. Nitrogen movement between host and tumor in mice inoculated with Ehrlich ascitic tumor cells. Cancer Res. CAS PubMed Google Scholar. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Zhang J, Pavlova NN, Thompson CB. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. EMBO J. Daye D, Wellen KE. Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol. Welbourne TC. Ammonia production and glutamine incorporation into glutathione in the functioning rat kidney. Can J Biochem. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA. Cheong H, Lindsten T, Wu J, Lu C, Thompson CB. Eng CH, Yu K, Lucas J, White E, Abraham RT. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, Lokshin M, Hosokawa H, Nakayama T, Suzuki Y, et al. Phosphate-activated glutaminase GLS2 , a pinducible regulator of glutamine metabolism and reactive oxygen species. Jackson JG, Lozano G. The mutant p53 mouse as a pre-clinical model. Tran TQ, Lowman XH, Reid MA, Mendez-Dorantes C, Pan M, Yang Y, Kong M. Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Dilshara MG, Jeong JW, Prasad Tharanga Jayasooriya RG, Neelaka Molagoda IM, Lee S, Park SR, Choi YH, Kim GY. Glutamine deprivation sensitizes human breast cancer MDA-MB cells to TRIAL-mediated apoptosis. Biochem Biophys Res Commun. Gaglio D, Soldati C, Vanoni M, Alberghina L, Chiaradonna F. Glutamine deprivation induces abortive s-phase rescued by deoxyribonucleotides in k-ras transformed fibroblasts. PLoS ONE. Gaglio D, Metallo CM, Gameiro PA, Hiller K, Danna LS, Balestrieri C, Alberghina L, Stephanopoulos G, Chiaradonna F. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol. Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL. The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. Faubert B, Vincent EE, Griss T, Samborska B, Izreig S, Svensson RU, Mamer OA, Avizonis D, Shackelford DB, Shaw RJ, Jones RG. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Biswas SK, Mantovani A. Orchestration of metabolism by macrophages. Ghesquière B, Wong BW, Kuchnio A, Carmeliet P. Metabolism of stromal and immune cells in health and disease. Article PubMed CAS Google Scholar. Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Hao S, Yan KK, Ding L, Qian C, Chi H, Yu J. Network approaches for dissecting the immune system. Article CAS Google Scholar. Ricciardi S, Manfrini N, Alfieri R, Calamita P, Crosti MC, Gallo S, Müller R, Pagani M, Abrignani S, Biffo S. Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Newsholme P. Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? J Nutr. Curi R, Newsholme P, Marzuca-Nassr GN, Takahashi HK, Hirabara SM, Cruzat V, Krause M, de Bittencourt Jr PI. Regulatory principles in metabolism-then and now. Biochem J. Cruzat V, Macedo Rogero M. Glutamine: metabolism and immune function, supplementation and clinical translation. Article PubMed Central CAS Google Scholar. Curi R, Lagranha CJ, Doi SQ, Sellitti DF, Procopio J, Pithon-Curi TC, Corless M, Newsholme P. Molecular mechanisms of glutamine action. J Cell Physiol. Curi R, Lagranha CJ, Doi SQ, Sellitti DF, Procopio J, Pithon-Curi TC. Glutamine-dependent changes in gene expression and protein activity. Cell Biochem Funct. Roth E, Oehler R, Manhart N, Exner R, Wessner B, Strasser E, Spittler A. Regulative potential of glutamine—relation to glutathione metabolism. Hiscock N, Petersen EW, Krzywkowski K, Boza J, Halkjaer-Kristensen J, Pedersen BK. Glutamine supplementation further enhances exercise-induced plasma IL J Appl Physiol. Google Scholar. Crawford J, Cohen HJ. The essential role of L-glutamine in lymphocyte differentiation in vitro. Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, Di Conza G, Cheng WC, Chou CH, Vavakova M, et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol. Kolb D, Kolishetti N. Metabolic modulation of the tumor microenvironment leads to multiple checkpoint inhibition and immune cell infiltration. ACS Nano. Palmer CS, Ostrowski M, Balderson B, Christian N, Crowe SM. Glucose metabolism regulates T cell activation, differentiation, and functions. Front Immunol. Sukumar M, Roychoudhuri R, Restifo NP. Nutrient competition: a new axis of tumor immunosuppression. Fu Q, Xu L, Wang Y, Jiang Q, Liu Z, Zhang J, Zhou Q, Zeng H, Tong S, Wang T, et al. Tumor-associated macrophage-derived interleukin interlinks kidney cancer glutamine addiction with immune evasion. Eur Urol. Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E, Aghvanyan A, Turay AM, Frauwirth KA. J Immunol. Yang R, Li X, Wu Y, Zhang G, Liu X, Li Y, Bao Y, Yang W. Yang WH, Qiu Y, Stamatatos O, Janowitz T, Lukey MJ. Enhancing the efficacy of glutamine metabolism inhibitors in cancer therapy. Trends Cancer. Reinfeld BI, Madden MZ. Cell-programmed nutrient partitioning in the tumour microenvironment. Yang L, Achreja A, Yeung TL, Mangala LS, Jiang D, Han C, Baddour J, Marini JC, Ni J, Nakahara R, et al. Targeting Stromal Glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Fan SJ, Kroeger B. Glutamine deprivation alters the origin and function of cancer cell exosomes. Ma G, Liang Y, Chen Y, Wang L, Li D, Liang Z, Wang X, Tian D, Yang X, Niu H. Mol Cancer Res. Wang L, Xu T, Yang X, Liang Z, Zhang J, Li D, Chen Y, Ma G, Wang Y, Liang Y, Niu H. Immunosuppression Induced by glutamine deprivation occurs via activating PD-L1 transcription in bladder cancer. Front Mol Biosci. Byun JK, Park M, Lee S, Yun JW, Lee J, Kim JS, Cho SJ, Jeon HJ, Lee IK, Choi YK, Park KG. Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity. Mol Cell. Qing G, Li B, Vu A, Skuli N, Walton ZE, Liu X, Mayes PA, Wise DR, Thompson CB, Maris JM, et al. ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation. Csibi A, Lee G, Yoon SO, Tong H, Ilter D, Elia I, Fendt SM, Roberts TM, Blenis J. Curr Biol. Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, Gouw AM, Baylot V, Gütgemann I, Eilers M, Felsher DW. MYC regulates the antitumor immune response through CD47 and PD-L1. Mukhopadhyay S, Vander Heiden MG, McCormick F. The metabolic landscape of RAS-driven cancers from biology to therapy. Nat Cancer. Coelho MA, de Carné TS, Rana S, Zecchin D, Moore C, Molina-Arcas M, East P, Spencer-Dene B, Nye E, Barnouin K, et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Chen J, Jiang CC, Jin L, Zhang XD. |
| Go to your regional site? | Under normal metabbolism conditions, LDHA Glutaminw the conversion of pyruvate to lactate. Glutamine synthetase as an early marker for hepatocellular carcinoma based on proteomic analysis Heart health awareness campaigns resected metabooism Glutamine and metabolism Gut-boosting foods. Therefore, Glutaimne SLC7A11 Safe appetite control metabolim promising metabo,ism option, and its efficacy can be increased by combining it with drugs that target glutaminolysis SLC1A5 is highly expressed in triple-negative breast cancer patients, correlating with poor survival in tumor-bearing mice [ 65 ]. Indeed, the role of ASNS in tumorigenesis and metastasis has been reported, and it is associated with poor survival in various types of breast cancer, non-small cell lung cancer NSCLCand sarcoma 3839 Pant, A. |
| Glutamine metabolism in cancer therapy | Oncogenic KRAS supports Anti-arthritic supplements cancer through Glutamie of nucleotide synthesis. SLC38A1 promotes Glutamije and migration of human colorectal cancer cells. Oncogene 38— Transcriptomic and immunohistochemical profiling of SLC6A14 in pancreatic ductal adenocarcinoma. SIRT5 regulation of ammonia-induced autophagy and mitophagy. |
| Glutamine - Wikipedia | Macropinocytosis also facilitates the survival of hypoxic HCC cells. Thus, HCC cells can internalize extracellular proteins by increasing the expression of a membrane ruffling protein called EH domain-containing protein 2, leading to resistance to glutamine deprivation under hypoxic conditions Although targeting macropinocytosis could be a key strategy for overcoming resistance to glutamine uptake blockade, further studies are necessary to examine whether macropinocytosis can overcome tumor cell resistance to glutamine antimetabolites or GLS inhibitors that target enzymes involved directly in glutamine metabolism. Limiting glutamine utilization regulates nutrient stress-response proteins and transcription factors. Sestrin2-mediated suppression of mTORC1 and mTORC2 activation reprograms lipid metabolism to limit ATP and NADPH consumption, thereby enabling cancer cells to survive under glutamine-depleted conditions. Other studies have shown that ROS production in response to glutamine deprivation increases the expression of pdependent genes Gadd45a, Cdkn1, and Sestrin2 via B55α or IKKβ , Upregulation of Gadd45a and Cdkn1 induces cell cycle arrest in response to glutamine deprivation, which alleviates oxidative stress and reduces energy consumption , The TME is a complex milieu that surrounds tumor cells, often providing immunosuppressive cover that facilitates immune invasion. Specifically, competition for nutrients or cell-intrinsic programming between cancer cells and immune cells induces nutrient deficiency and metabolic reprogramming of immune cells, leading to modulation of antitumor immunity , Given that activation and differentiation of immune cells are coupled to metabolic reprogramming, regulating the metabolic activity of immune cells should be considered in the development of potential strategies that target glutamine metabolism , Accumulating evidence shows that glutamine is an immunomodulatory nutrient in immune cells. Naïve T cells are metabolically quiescent, undergoing basal levels of glycolysis and glutaminolysis sufficient to maintain minimal biosynthesis; however, T-cell receptor TCR -stimulated activation increases the expression of the Myc transcription factor, glutamine transporters SLC38A1, SLC38A2 , and glutaminolysis-related enzymes GLS, GLUD1, GOT, GPT to meet bioenergetic and biosynthetic requirements, resulting in T-cell proliferation , , , Mechanistically, α-KG decreases Treg differentiation by inhibiting FOXP3 and upregulating inflammatory cytokines such as IFN-γ, Tbet, and Rorc, suggesting that Th1-type effector T cells are more dependent on glutaminolysis than Treg cells Moreover, effector T cells are capable of adapting their metabolism in response to nutrient limitation. Activated T cells rely on glutamine-dependent OXPHOS to maintain energetic homeostasis under energy-related stress e. Although amino acids are essential for the function of NK cells, their main role in NK cells is the maintenance of signaling e. Unlike other lymphocyte subsets, glutaminolysis and the TCA cycle do not sustain OXPHOS in activated NK cells. Glutamine withdrawal, but not inhibition of glutaminolysis, results in loss of c-Myc protein, reduced cell growth, and impaired NK cell responses Consistent with this, receptor-simulated production of IFN-γ by NK cells is not impaired under glutamine-limited conditions In macrophages, glutamine metabolism is a critical metabolic pathway for differentiation. Macrophages undergo metabolic switching during differentiation into inflammatory M1 or anti-inflammatory M2 phenotypes. Tumor-associated macrophages TAMs can exhibit either an antitumor M1-like phenotype or a protumor M2-like phenotype. Glutamine starvation inhibits M2 polarization but not M1 polarization by suppressing UDP-GlcNAc biosynthesis and N-glycosylation of M2-related proteins such as Relmα, CD, and CD Consistent with this, glutaminolysis-derived α-KG promotes M2 activation by increasing fatty acid oxidation and Jmjd3-dependent epigenetic reprogramming of M2-related genes In contrast to the inhibition of glutaminolysis, pharmacological or genetic targeting of GLUL in macrophages reprograms M2-polarized macrophages to an M1-polarized phenotype Mechanistically, macrophage-specific inhibition of GLUL leads to accumulation of succinate and HIF-1α via glutamine-dependent γ-aminobutyric acid GABA shunting thereby inhibiting vessel sprouting and metastasis and via stimulation of T effector cells; however, ILinduced expression of GLUL promotes vessel sprouting, immunosuppression, and metastasis Given the importance of glutamine metabolism to immune cells, including activated lymphocytes, it is crucial to determine whether blockade of glutamine metabolism in tumor cells hampers anticancer immune responses; the answer may be key to the success of therapeutic strategies targeting glutamine metabolism. The metabolism of cancer cells and immune cells in the TME is regulated by cell-intrinsic programs through mTORC1 signaling PET tracers showed that cancer cells rely heavily on glutamine uptake via mTORC1 signaling, while myeloid cells in the TME are more dependent on glucose, as are T cells and cancer cells but to a lesser extent Accumulating evidence shows that inhibitors of glutamine metabolism, such as V, JHU, and CB, elicit stronger antitumor effects when used in combination with immune checkpoint inhibitors , , Fig. In a previous study, we showed that V induces the expression of PD-L1 by tumor cells and augments immune evasion in synergistic murine models Therefore, agents that target glutamine utilization may, when used in combination with an anti-PD-L1 antibody, boost antitumor immunity Similar results were reported for several tumors , , , Furthermore, bladder tumors in mice supplemented with glutamine showed lower PD-L1 levels than control tumors As a therapeutic option, combined treatment with asparaginase and an anti-PD-1 antibody could be useful because glutamine-addicted cells are sensitive to asparaginase PD-L1 suppresses antitumor immune responses by blocking T-cell activation in the tumor microenvironment. b Treatment with glutamine analogs, including DON and JHU, decreases glucose and glutamine metabolism, leading to inhibition of tumor growth via a decrease in hypoxia, acidosis, and nutrient depletion in the tumor microenvironment. Furthermore, DON decreases the recruitment of MDSCs by suppressing the secretion of CSF3 by tumor cells and blocking the production of the immunosuppressive metabolite kynurenine; this inhibits the synthesis of the hyaluronan-rich ECM, resulting in the activation and infiltration of T cells. PD-L1, programmed death-ligand 1; CSF3, colony stimulating factor 3; MDSC, myeloid-derived suppressor cell; ECM, extracellular matrix. Another study showed that in JHUtreated cancer cell allograft models, an increase in nutrient levels and oxygen and a decrease in the acidity of the TME resulted in T-cell-mediated tumor suppression , whereas another study demonstrated the effects of JHU on myeloid-derived suppressor cells MDSCs and TAMs Glutamine metabolism plays a central role in regulating uncontrolled tumor growth by modulating bioenergetic and redox homeostasis and by serving as a precursor for the synthesis of biomass. Although targeting glutamine metabolism is a promising strategy for cancer therapy, there are many hurdles to be overcome before we develop a clinically effective drug. Metabolic flexibility or adaptation by cancer cells, as well as reduced antitumor immunity, may be unwanted consequences of inhibiting glutamine metabolism. A comprehensive understanding of the TME is of the utmost importance because it provides valuable insights into pathways that could be targeted by novel metabolic therapies for advanced or drug-resistant cancers. Ward, P. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 21 , — Article CAS PubMed PubMed Central Google Scholar. Stine, Z. Targeting cancer metabolism in the era of precision oncology. Drug Discov. Article CAS PubMed Google Scholar. Wang, Z. et al. Targeting glutaminolysis: new perspectives to understand cancer development and novel strategies for potential target therapies. Article PubMed PubMed Central Google Scholar. Cruzat, V. Glutamine: metabolism and immune function, supplementation and clinical translation. Nutrients 10 , Altman, B. From Krebs to clinic: glutamine metabolism to cancer therapy. Cancer 16 , — Matés, J. Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer. Cell Dev. Article PubMed Google Scholar. Ma, G. Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment. Cell Commun. Choi, Y. Targeting glutamine metabolism for cancer treatment. Seoul 26 , 19—28 Grinde, M. Glutamine to proline conversion is associated with response to glutaminase inhibition in breast cancer. Breast Cancer Res. Xiang, L. Glutaminase 1 expression in colorectal cancer cells is induced by hypoxia and required for tumor growth, invasion, and metastatic colonization. Cell Death Dis. Gao, P. Nature , — Csibi, A. Zhang, C. Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis. Elife 5 , e Saha, S. Multiomics analysis reveals that GLS and GLS2 differentially modulate the clinical outcomes of cancer. Dias, M. GLS2 is protumorigenic in breast cancers. Oncogene 39 , — Knock-down of glutaminase 2 expression decreases glutathione, NADH, and sensitizes cervical cancer to ionizing radiation. Cell Res. Article CAS Google Scholar. López de la Oliva, A. Nuclear translocation of glutaminase GLS2 in human cancer cells associates with proliferation arrest and differentiation. Cardaci, S. TCA cycle defects and cancer: when metabolism tunes redox state. Cell Biol. Jin, L. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27 , — Yelamanchi, S. A pathway map of glutamate metabolism. Signal 10 , 69—75 Vanhove, K. Glutamine addiction and therapeutic strategies in lung cancer. Yang, M. Oncometabolites: linking altered metabolism with cancer. Wang, Q. Therapeutic targeting of glutamate dehydrogenase 1 that links metabolic reprogramming and Snail-mediated epithelial—mesenchymal transition in drug-resistant lung cancer. Tambay, V. MYC rules: leading glutamine metabolism toward a distinct cancer cell phenotype. Cancers Basel 13 , Wei, Z. Metabolism of amino acids in cancer. Yuan, H. Nutrient sensing, metabolism, and cell growth control. Cell 49 , — Ahn, C. Mitochondria as biosynthetic factories for cancer proliferation. Cancer Metab. Korangath, P. Targeting glutamine metabolism in breast cancer with aminooxyacetatetargeting glutamine metabolism in breast cancer. Cancer Res. Zhang, B. GPT2 is induced by hypoxia-inducible factor HIF -2 and promotes glioblastoma growth. Cells 11 , Kim, M. Mitochondrial GPT2 plays a pivotal role in metabolic adaptation to the perturbation of mitochondrial glutamine metabolism. Oncogene 38 , — Shen, Y. A novel signature derived from metabolism-related genes GPT and SMS to predict prognosis of laryngeal squamous cell carcinoma. Cancer Cell Int. Gorgoglione, R. Glutamine-derived aspartate biosynthesis in cancer cells: role of mitochondrial transporters and new therapeutic perspectives. Cancers Basel 14 , Yang, H. SIRT3-dependent GOT2 acetylation status affects the malate—aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J. Sun, W. Aspulvinone O, a natural inhibitor of GOT1 suppresses pancreatic ductal adenocarcinoma cells growth by interfering glutamine metabolism. Signal 17 , Kerk, S. Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context. eLife 11 , e Kilberg, M. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol. Krall, A. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Knott, S. Asparagine bioavailability governs metastasis in a model of breast cancer. Cai, D. Asparagine synthetase regulates lung-cancer metastasis by stabilizing the β-catenin complex and modulating mitochondrial response. Hettmer, S. Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. Elife 4 , e Yang, W. Enhancing the efficacy of glutamine metabolism inhibitors in cancer therapy. Trends Cancer 7 , — Shukla, K. Design, synthesis, and pharmacological evaluation of bis 5-phenylacetamido-1,2,4-thiadiazolyl ethyl sulfide 3 BPTES analogs as glutaminase inhibitors. Hudson, C. Altered glutamine metabolism in platinum resistant ovarian cancer. Oncotarget 7 , — Chen, P. Targeting YTHDF1 effectively re-sensitizes cisplatin-resistant colon cancer cells by modulating GLS-mediated glutamine metabolism. Oncolytics 20 , — Biancur, D. Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Varghese, S. The glutaminase inhibitor CB Telaglenastat enhances the antimelanoma activity of T-cell—mediated immunotherapies. Cancer Ther. Wicker, C. Glutaminase inhibition with telaglenastat CB improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models. Cancer Lett. Boysen, G. Glutaminase inhibitor CB increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice. Peeters, T. Isocitrate dehydrogenase 1-mutated cancers are sensitive to the green tea polyphenol epigallocatechingallate. Bansal, A. Glutathione metabolism in cancer progression and treatment resistance. Huang, R. Dual role of reactive oxygen species and their application in cancer therapy. Cancer 12 , — Lv, H. Unraveling the potential role of glutathione in multiple forms of cell death in cancer therapy. Cell Longev. Anderson, M. Glutathione: an overview of biosynthesis and modulation. Kang, Y. Non-canonical glutamate-cysteine ligase activity protects against ferroptosis. Cell Metab. e7 Koppula, P. Protein Cell 12 , — Son, J. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Keppler, D. Export pumps for glutathione S-conjugates. Free Radic. Byun, J. Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity. Cell 80 , — e8 Bannai, S. A novel function of glutamine in cell culture: Utilization of glutamine for the uptake of cystine in human fibroblasts. Timmerman, L. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24 , — Muir, A. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. Elife 6 , e Jyotsana, N. Badgley, M. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science , 85—89 Yan, R. The structure of erastin-bound xCT—4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis. Zhang, Y. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem. e9 Kremer, D. GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis. Zhang, L. Acta Pharmacol. PubMed PubMed Central Google Scholar. Bhutia, Y. Glutamine transporters in mammalian cells and their functions in physiology and cancer. Acta , — Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. Willems, L. Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. Blood , — Cha, Y. Amino acid transporters and glutamine metabolism in breast cancer. Hassanein, M. SLC1A5 mediates glutamine transport required for lung cancer cell growth and survival. Scalise, M. Cysteine of the ASCT2 amino acid transporter is a molecular determinant of the antiport mechanism. Sastrasinh, M. Effect of acute pH change on mitochondrial glutamine transport. CAS PubMed Google Scholar. Li, X. Role of glutamine and its metabolite ammonia in crosstalk of cancer-associated fibroblasts and cancer cells. van Geldermalsen, M. Oncogene 35 , — Kahya, U. Amino Acid Transporters on the Guard of Cell Genome and Epigenome. Zhou, X. Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol —9. Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JR, Ackrell BA, Brand MD. Mitochondrial complex II can generate reactive oxygen species at high rates in both the forward and reverse reactions. J Biol Chem — Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discovery. CrossRef Full Text Google Scholar. Panieri E, Santoro MM. ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Disease. Kröller-Schön S, Steven S, Kossmann S, Scholz A, Daub S, Oelze M, et al. Molecular mechanisms of the crosstalk between mitochondria and NADPH oxidase through reactive oxygen species-studies in white blood cells and in animal models. Antioxidants Redox Signaling — Warburg O. On the origin of cancer cells. Sci New York NY. Sosa V, Moliné T, Somoza R, Paciucci R, Kondoh H, Lleonart ME. Oxidative stress and cancer: An overview. Ageing Res Rev — Herraiz C, Crosas-Molist E, Sanz-Moreno V. Reactive oxygen species and tumor dissemination: Allies no longer. Mol Cell Oncol 3:e Maryanovich M, Gross A. A ROS rheostat for cell fate regulation. Trends Cell Biol — Hayes JD, Dinkova-Kostova AT, Tew KD. Oxidative stress in cancer. Cancer Cell — Kodama M, Oshikawa K, Shimizu H, Yoshioka S, Takahashi M, Izumi Y, et al. A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer. Nat Commun DeBerardinis RJ, Cheng T. Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene — Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. Franklin CC, Backos DS, Mohar I, White CC, Forman HJ, Kavanagh TJ. Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase. Mol aspects Med — Kennedy L, Sandhu JK, Harper ME, Cuperlovic-Culf M. Role of glutathione in cancer: From mechanisms to therapies. Biomolecules Lu SC. Regulation of glutathione synthesis. van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, et al. Oncogene —8. Jiang H, Zhang N, Tang T, Feng F, Sun H, Qu W. Pharmacol Res Bhutia YD, Ganapathy V. Glutamine transporters in mammalian cells and their functions in physiology and cancer. Biochim Biophys Acta —9. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. Nature —5. Hu W, Zhang C, Wu R, Sun Y, Levine A, Feng Z. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Lukey MJ, Greene KS, Erickson JW, Wilson KF, Cerione RA. The oncogenic transcription factor c-jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy. Suzuki S, Tanaka T, Poyurovsky MV, Nagano H, Mayama T, Ohkubo S, et al. Phosphate-activated glutaminase GLS2 , a pinducible regulator of glutamine metabolism and reactive oxygen species. Proc Natl Acad Sci USA —6. Zhang J, Pavlova NN, Thompson CB. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. EMBO J — Koppula P, Zhang Y, Zhuang L, Gan B. Cancer Commun London England. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Ying M, You D, Zhu X, Cai L, Zeng S, Hu X. Lactate and glutamine support NADPH generation in cancer cells under glucose deprived conditions. Redox Biol Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Moreno-Sánchez R, Gallardo-Pérez JC, Rodríguez-Enríquez S, Saavedra E, Marín-Hernández Á. Control of the NADPH supply for oxidative stress handling in cancer cells. Free Radic Biol Med. Bansal A, Simon MC. Glutathione metabolism in cancer progression and treatment resistance. J Cell Biol —8. Jaganjac M, Milkovic L, Sunjic SB, Zarkovic N. The NRF2, thioredoxin, and glutathione system in tumorigenesis and anticancer therapies. Antioxidants Basel Switzerland. Palde PB, Carroll KS. A universal entropy-driven mechanism for thioredoxin-target recognition. Proc Natl Acad Sci USA —5. Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet London England. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, CA: Cancer J Clin — Park W, Chawla A, O'Reilly EM. Pancreatic cancer: A review. Jama — Li W, Chen C, Zhao X, Ye H, Zhao Y, Fu Z, et al. J Cell Mol Med — Tong Y, Guo D, Lin SH, Liang J, Yang D, Ma C, et al. SUCLA2-coupled regulation of GLS succinylation and activity counteracts oxidative stress in tumor cells. Mol Cell — Hu T, Shukla SK, Vernucci E, He C, Wang D, King RJ, et al. Metabolic rewiring by loss of Sirt5 promotes kras-induced pancreatic cancer progression. Gastroenterology — Wang YP, Zhou W, Wang J, Huang X, Zuo Y, Wang TS, et al. Arginine methylation of MDH1 by CARM1 inhibits glutamine metabolism and suppresses pancreatic cancer. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, et al. Oncogenic kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell — Raho S, Capobianco L, Malivindi R, Vozza A, Piazzolla C, De Leonardis F, et al. KRAS-regulated glutamine metabolism requires UCP2-mediated aspartate transport to support pancreatic cancer growth. Nat Metab — Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, et al. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood — Willems L, Jacque N, Jacquel A, Neveux N, Maciel TT, Lambert M, et al. Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. Gallipoli P, Giotopoulos G, Tzelepis K, Costa ASH, Vohra S, Medina-Perez P, et al. Glutaminolysis is a metabolic dependency in FLT3 ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition. Matre P, Velez J, Jacamo R, Qi Y, Su X, Cai T, et al. Inhibiting glutaminase in acute myeloid leukemia: metabolic dependency of selected AML subtypes. Oncotarget — Gregory MA, Nemkov T, Reisz JA, Zaberezhnyy V, Hansen KC, D'Alessandro A, et al. Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia. Exp hematology. Gregory MA, D'Alessandro A, Alvarez-Calderon F, Kim J, Nemkov T, Adane B, et al. Proc Natl Acad Sci USA E—e Gregory MA, Nemkov T, Park HJ, Zaberezhnyy V, Gehrke S, Adane B, et al. Targeting glutamine metabolism and redox state for leukemia therapy. Clin Cancer Res — Bezjak A, Temin S, Franklin G, Giaccone G, Govindan R, Johnson ML, et al. Definitive and adjuvant radiotherapy in locally advanced non-Small-Cell lung cancer: American society of clinical oncology clinical practice guideline endorsement of the American society for radiation oncology evidence-based clinical practice guideline. J Clin Oncol —5. Cheema PK, Rothenstein J, Melosky B, Brade A, Hirsh V. Perspectives on treatment advances for stage III locally advanced unresectable non-small-cell lung cancer. Curr Oncol Toronto Ont. Cassidy RJ, Zhang X, Patel PR, Shelton JW, Escott CE, Sica GL, et al. Next-generation sequencing and clinical outcomes of patients with lung adenocarcinoma treated with stereotactic body radiotherapy. Cancer — Jeong Y, Hoang NT, Lovejoy A, Stehr H, Newman AM, Gentles AJ, et al. Cancer Discovery. Gurtner K, Kryzmien Z, Koi L, Wang M, Benes CH, Hering S, et al. Int J Cancer —7. Mak RH, Hermann G, Lewis JH, Aerts HJ, Baldini EH, Chen AB, et al. Outcomes by tumor histology and KRAS mutation status after lung stereotactic body radiation therapy for early-stage non-small-cell lung cancer. Clin Lung cancer. Sitthideatphaiboon P, Galan-Cobo A, Negrao MV, Qu X, Poteete A, Zhang F, et al. Boysen G, Jamshidi-Parsian A, Davis MA, Siegel ER, Simecka CM, Kore RA, et al. Glutaminase inhibitor CB increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice. Int J Radiat Biol — Sappington DR, Siegel ER, Hiatt G, Desai A, Penney RB, Jamshidi-Parsian A, et al. Glutamine drives glutathione synthesis and contributes to radiation sensitivity of A and H lung cancer cell lines. Biochim Biophys Acta — Fujimoto M, Higashiyama R, Yasui H, Yamashita K, Inanami O. Preclinical studies for improving radiosensitivity of non-small cell lung cancer cell lines by combining glutaminase inhibition and senolysis. Trans Oncol Meijer TWH, Peeters WJM, Dubois LJ, van Gisbergen MW, Biemans R, Venhuizen JH, et al. Targeting glucose and glutamine metabolism combined with radiation therapy in non-small cell lung cancer. Lung Cancer Amsterdam Netherlands. Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, et al. median 11 days. Common side effects of L-glutamine oral powder include constipation, nausea, headache, abdominal pain, cough, pain in the extremities, back pain and chest pain. L-glutamine oral powder received orphan drug designation. Glutamine is marketed as medical food and is prescribed when a medical professional believes a person in their care needs supplementary glutamine due to metabolic demands beyond what can be met by endogenous synthesis or diet. Glutamine is safe in adults and in preterm infants. Adverse effects of glutamine have been described for people receiving home parenteral nutrition and those with liver-function abnormalities. Ceasing glutamine supplementation in people adapted to very high consumption may initiate a withdrawal effect, raising the risk of health problems such as infections or impaired integrity of the intestine. Glutamine can exist in either of two enantiomeric forms, L -glutamine and D -glutamine. The L -form is found in nature. Glutamine mouthwash may be useful to prevent oral mucositis in people undergoing chemotherapy but intravenous glutamine does not appear useful to prevent mucositis in the GI tract. Glutamine supplementation was thought to have potential to reduce complications in people who are critically ill or who have had abdominal surgery but this was based on poor quality clinical trials. Some athletes use L -glutamine as supplement. Studies support the positive effects of the chronic oral administration of the supplement on the injury and inflammation induced by intense aerobic and exhaustive exercise, but the effects on muscle recovery from weight training are unclear. Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item. Download as PDF Printable version. In other projects. Wikimedia Commons. For other uses, see GLN disambiguation. Not to be confused with Glutamic acid or Glutaric acid. Skeletal formula of L -glutamine. Ball-and-stick model. Space-filling model. L-Glutamine levo glutamide 2,5-Diaminooxopentanoic acid 2-Aminocarbamoylbutanoic acid Endari [1]. CAS Number. Interactive image Zwitterion : Interactive image. CHEBI Y. ChEMBL Y. DB Y. C Y. PubChem CID. CompTox Dashboard EPA. Chemical formula. Solubility in water. Chiral rotation [α] D. ATC code. Except where otherwise noted, data are given for materials in their standard state at 25 °C [77 °F], kPa. Infobox references. Chemical compound. US DailyMed : Glutamine. A16AA03 WHO. IUPAC name. D C GLN PDBe , RCSB PDB. Interactive image. This section is missing information about possible mechanism of action, pharmacokinetics in PMID Please expand the section to include this information. Further details may exist on the talk page. November Food and Drug Administration FDA Press release. Retrieved 10 July This article incorporates text from this source, which is in the public domain. |
Ich verstehe etwas nicht