Ribose in cancer prevention -
Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA. Department of Pathology and Clinical Labs, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Centre for Global Oncology, Division of Molecular Pathology, The Institute of Cancer Research, London, UK. You can also search for this author in PubMed Google Scholar. designed the study. wrote the manuscript. designed experiments, and Z. and P. collected data for the bulk of the experimental studies.
prepared manuscript figures. and Z. carried out the initial cell line screen, and P. conducted the analysis of the screening data that revealed lead metabolite—enzyme interactions. carried out experiments. and E. contributed to the data analysis. provided resources, funding and conceptual input for experiments and supervised the research.
All authors reviewed and approved the final manuscript. Correspondence to Anguraj Sadanandam or Costas A. Nature thanks the anonymous reviewers for their contribution to the peer review of this work.
Peer review reports are available. Schematic overview of the parameters measured by the Biolog Phenotype Microarray. Heatmap showing the high confidence metabolites HCMs , namely, the metabolites that were utilized above or below the median of negative controls as determined by one-tailed Wilcoxon rank sum test.
Legend denotes fold change relative to median negative control signal, where red shows high utilization and blue shows low utilization. Spearman correlations, r, between UPP1 expression in cell lines ref.
On the right: GSEA plot indicating the enrichment of glycolysis hallmark in the UPP1 high relative to the low tumours. NES, normalized enrichment score. Analysis was based on the differential genes derived from CCLE data and part of the data shown in Fig. GSEA plots of significantly enriched KEGG pathways in UPP1 -high PDA tumours relative to UPP1 low tumours.
Plots are part of the data e from the analysis of GSE human PDA dataset. Statistics and reproducibility: a , The kinetic measurement evaluated several parameters, including the time taken for cells to adapt to and catabolize a nutrient lambda , the rate of uptake and catabolism mu or slope , the total metabolic activity area under the curve; AUC , and the maximum metabolic activity.
The values from the maximum catabolic efficiency maximum height, A of the respective metabolites were used to determine relative metabolic activity RMA.
Relative RMA upon uridine supplementation with or without glucose and glutamine. Plots in f-g are from the same experiment as d-e.
Statistical significance was measured using two-tailed unpaired t-test. Data a, f, g, h are shown as mean ± s. ADP, adenosine diphosphate; AMP, adenosine monophosphate; GSSG, oxidized glutathione; NADH, nicotinamide adenine dinucleotide; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; X5P, xylulose 5-phosphate.
Mode of uridine injection is intratumoural for Sub-Q and intraperitoneal for Ortho. Isotope tracing showing metabolite labelling upon supplementation with 13 C 5 -uridine at the TIF uridine and glucose concentrations shown in Fig.
AXP — AMP, ADP, ATP, and related metabolites; UXP — UMP, UDP, UTP and related metabolites. The experiments a-d were performed once. Data a-d are shown as mean ± s. d, where applicable. Schematic depicting metabolic pathways for uridine utilization. Expression of PGM2 , UCK1 , and UCK2 in non-tumour NT and PDA tissue samples from the GSE dataset.
Expression of PGM2 , UCK1 and UCK2 in TCGA human PDA tumour and CCLE human cell line data separated into UPP1 low L and high H subsets.
Western blot for PGM2 in PDA cell lines. Presented in bold are cells that express high UPP1. These samples are the same batch as the data shown in Fig. kDa, unit for molecular weight. qPCR for PGM2 in ASPC1 cells transfected with siPGM2 compared to non-targeting siNT control.
qPCR for UCK1 in ASPC1 cells transfected with siUCK1 compared to non-targeting siNT control. qPCR for UCK2 in ASPC1 cells transfected with siUCK2 compared to non-targeting siNT control. All four group comparisons have significant P: 0. Uridine can also be catabolized via UPP1 to produce uracil and ribose 1-phosphate.
Ribose 1-phosphate is converted to ribosephosphate by PGM2 and fuel pentose phosphate pathway, nucleotide biosynthesis and glycolysis. TCGA — The Cancer Genome Atlas, CCLE — Cancer Cell Line Encyclopaedia.
Vinculin is used as a loading control. RMA — statistical significance was measured using multiple unpaired t tests with two-stage two-step method. Data a—c, f—h, j—l are shown as mean ± s. The experiments were performed once a—c, k , and twice j,l with similar results.
Mass isotopologue distribution of 1 mM 13 C 5 -uridine ribose-derived carbon into the indicated metabolic pathways in wildtype WT or UPP1-KO PATUS and ASPC1 cells.
Data a—b, d—k are shown as mean ± s. Metabolomics experiments were done once. TCGA RNA seq data showing the expression of UPP1 and its paralog UPP2.
FPKM, fragments per kilobase of exon per million mapped fragments. RNA seq showing UPP1 expression in various normal human tissues Human Protein Atlas data , as obtained from the National Center for Biotechnology Information NCBI portal.
Histological data showing UPP1 protein expression in normal pancreatic tissue compared to PDA. UPP1 expression in human non-PDA cancers accessed in publicly accessible datasets. A lung cancer cell line, comparison between no uridine and 0. RPKM, reads per kilobase of exon per million reads mapped.
Data a-b, f shown as mean ± s. Statistical significance was tested using two-sided Wilcoxon or Kruskal-Wallis tests. RNAscope images showing UPP1 expression in tumour PDA compared to the adjacent non-tumour tissues. Pan-cytokeratin PanCK indicates the tumour cells; DAPI, nuclear stain.
The images are representative of three 20x acquisitions per tissue slide, and of two independent experiments. Scale bar indicates µm. UMAP plot showing the expression of UPP1 at the transcript level, as determined by single cell RNA seq of PDA tissues from two patients and Violin plots showing UPP1 expression in various tumour microenvironment cell types, including myeloid and epithelial cells where UPP1 is highest.
Data used in plots b-c are from a previously published dataset Immunohistochemistry of UPP1 in patient biopsy sections from previously published tissue microarray Micrographs are representative from patient samples in the microarray and two independent experiments. Kaplan-Meier plot showing survival probability log-rank test based on UPP1 expression in three separate datasets.
Each dataset was split into two — UPP1 high and UPP1 low — based on the ranked UPP1 expression value. TME — tumour microenvironment.
Normalized UPP1 protein expression in Kras wildtype and mutant cell lines based on CCLE protein data accessed via the DepMap portal. Densitometric quantification of pERK and UPP1 in the ASPC1 blots shown in Fig. MTT assay showing relative proliferation of PDA cell lines treated with 1.
Statistics and reproducibility: a , Sample size — wild type 0 and mutation 1: and 69 pan-cancer , 15 and 15 colon cancer , 54 and 25 lung cancer. Statistical significance was measured using two-tailed unpaired t test.
ERK and Vinculin are used as loading controls. Blots are representative of two biological and technical replicates for ASPC1 and one biological replicate for PATUS and DANG with similar results. The experiments e, g, h were performed once with similar results on UPP1 displayed by the three cell lines.
This blot was run on the same gel as Fig. Blots c,i are representative of two independent experiments; blot e experiment was done once. Data b, e, g-h, l shown as mean ± s.
On the right: UPP1 mRNA expression determined by qPCR. CiiDER analysis of transcription factor binding sites in the promoters of mouse and human UPP1. Myc binding sites were not detected. qPCR showing UPP1 expression upon uridine supplementation with or without basal glucose concentration in culture medium.
RNA seq data showing the expression of Upp1 in sorted tumour cells and in KPC cells cultured in vitro in regular RPMI culture medium or tumour interstitial fluid medium TIFM. Blots shown a-b are representative of two biological and technical replicate analyses with similar results.
Data a,b,d,e shown as mean ± s. Data was extracted from a previously published metabolomics Relative uracil abundance in plasma, tumour interstitial fluid TIF , and bulk tumour from the experiment described in Fig.
Micrographs are representative of 10 fields per image obtained per experiment group. On the right is the respective quantification of each IHC stain.
Color scale denotes fold change. Below: Venn diagram showing overlapping metabolites that accumulated in both human PATUS and ASPC1 and mouse MTD cell lines upon UPP1 knockout. On the right: bulk tumour uridine and uracil as measured using metabolomics.
Data a, b, d, e shown as mean ± s. d; horizontal bars in h represent mean value. Source data for metabolomics, mouse studies and qPCR. Full source data for all the metabolomics and tumour studies are presented, labelled by sub-figure and separated by tabs.
Additionally, mRNA expression is provided for PGM2 , UCK1 and UCK2 following siRNA-mediated knockdown. Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions.
Nwosu, Z. Uridine-derived ribose fuels glucose-restricted pancreatic cancer. Download citation. Received : 21 June Accepted : 12 April Published : 17 May Issue Date : 01 June Anyone you share the following link with will be able to read this content:.
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Skip to main content Thank you for visiting nature. nature articles article. Download PDF. Subjects Cancer metabolism Metabolomics Pancreatic cancer. Abstract Pancreatic ductal adenocarcinoma PDA is a lethal disease notoriously resistant to therapy 1 , 2. Main PDA remains one of the deadliest cancers 1 , 2.
Nutrient-deprived PDA consumes uridine To screen for metabolites that fuel metabolism in nutrient-deprived PDA cells, we applied the Biolog phenotypic screening platform on 19 human PDA cell lines and 2 immortalized, non-malignant pancreas cell lines human pancreatic stellate cells and human pancreatic nestin-expressing cells Fig.
Full size image. Uridine consumption correlates with UPP1 To select lead metabolites for investigation, we correlated metabolite utilization patterns to the expression of metabolism-associated genes using a public dataset 17 , Uridine-derived ribose fuels metabolism Our screen Fig.
UPP1 provides uridine-derived ribose To confirm the role of UPP1 in uridine catabolism, we knocked out UPP1 UPP1-KO using CRISPR—Cas9 in the PATUS UPP1-low and ASPC1 UPP1-high human PDA cell lines and validated two independent clones per cell line Fig. High UPP1 in PDA predicts poor survival To further assess the relevance of UPP1 in PDA tumours, we next analysed its expression in publicly available human PDA datasets.
KRAS—MAPK pathway regulates UPP1 KRAS mutations are the signature transforming event observed in the majority of PDAs Nutrient availability modulates UPP1 Given that glucose availability influences the use of uridine-derived ribose, we hypothesized that a glucose-depleted microenvironment triggers PDA to upregulate UPP1 as a compensatory response.
UPP1-KO blunts PDA tumour growth Uridine concentration is reported to be around twofold higher in TIF than in plasma Discussion The metabolic features of PDA drive disease aggression and therapeutic resistance and present new opportunities for therapy 2 , 6.
Methods Cell culture The PDA cell lines A, HT, HCT and U2OS and human pancreatic nestin-expressing cells were purchased from the American Type Culture Collection ATCC or the German Collection of Microorganisms DSMZ. Biolog metabolic assay In the initial phenotypic screen, the 22 cell lines were grown in well PM-M1 and PM-M2 plates Biolog, and Correlation of Biolog metabolites to gene expression of enzymes High-confidence metabolites from the Biolog screening assay were correlated Spearman Correlation to gene expression data for enzymes associated with metabolite usage.
NADH assay Cells were seeded in well plates at 10, cells per well directly into the indicated medium conditions. CyQUANT proliferation assay Cells were seeded at 20, cells per well for the screening study or 2, cells per well for proliferation assays in growth medium in well plates Corning, UPP1 CRISPR—Cas9 knockout The expression vector pspCas9 BB -2A-Puro PX used to generate the UPP1 CRISPR—Cas9 constructs was obtained from Addgene Plasmid Western blotting Following culture, medium was aspirated, and the wells washed one time with PBS.
Mouse tumour studies Animal studies were performed at the University of Michigan, the Institute of Cancer Research ICR , and the University of Chicago according to approved protocols. TIF collection TIF was isolated from tumours as described In vivo delivery of isotopically labelled uridine Uridine-derived ribose carbon was traced in vivo using [ 13 C 5 ]ribose-labelled uridine Cambridge Isotope Laboratories, CLMPK.
Stable isotope tracing For stable isotope tracing in cells, [ 13 C 5 ]uridine Cambridge Isotope Laboratories, CLMPK was supplemented at 0. Quantification of TIF metabolite levels For quantification of uridine and glucose in TIF, quantitative metabolite profiling of fluid samples was performed as previously described Clinical samples Patients with pancreas resections for PDA from to at the University of Michigan Health System were included in the study.
Tissue microarrays All specimens are from patients with pancreas resections for pancreatitis, cystic neoplasms, or PDA from to at the University of Michigan Health System.
Immunohistochemistry Patients tissue slides were deparaffinized and rehydrated with graded Histo-Clear National Diagnostics , ethanol, and water.
Pan-cancer dataset analysis TCGA pan-cancer datasets including bladder, colon, oesophageal, lung, head and neck, prostate cancer and glioblastoma, were downloaded from Xena Platform from University of California Santa Cruz CCLE gene analysis and PDA tumour data stratification Gene expression data for uridine high and uridine low metabolizers were extracted from the CCLE GSE Promoter analysis of UPP1 CiiDER 54 was used for predicting UPP1 gene transcription factor sites.
Statistical analysis Statistics were performed either with GraphPad Prism 8 GraphPad Software Inc. Statistics and reproducibility Figure 1. Reporting summary Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.
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Author information Author notes These authors contributed equally: Zeribe C. Ward, Peter Sajjakulnukit, Pawan Poudel Authors and Affiliations Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA Zeribe C. Lyssiotis Department of Chemistry, Washington University in St Louis, St Louis, MO, USA Matthew H.
Patti Department of Medicine, Washington University in St Louis, St Louis, MO, USA Matthew H. Patti Center for Metabolomics and Isotope Tracing, Washington University in St Louis, St Louis, MO, USA Matthew H.
Menjivar Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA Juan J. Lyssiotis Centre for Global Oncology, Division of Molecular Pathology, The Institute of Cancer Research, London, UK Anguraj Sadanandam Authors Zeribe C.
Nwosu View author publications. View author publications. Ethics declarations Competing interests C. Peer review Peer review information Nature thanks the anonymous reviewers for their contribution to the peer review of this work.
Extended data figures and tables. Extended Data Fig. Supplementary information Reporting Summary. Peer Review File. Supplementary Figure 1 Full, uncropped western images for Fig. Supplementary Figure 2 Full, uncropped western images for Fig. Supplementary Figure 3 Full, uncropped western images for Fig.
Supplementary Figure 4 Full, uncropped western images for Fig. Supplementary Figure 5 Full, uncropped western images for Extended Data Fig.
Supplementary Figure 6 Full, uncropped western images for Extended Data Fig. Supplementary Figure 7 Full, uncropped western images for DANG cell line in Extended Data Fig. Supplementary Figure 8 Full, uncropped western image for TUS cell line in Extended Data Fig.
Supplementary Figure 9 Full, uncropped western images for Extended Data Fig. Supplementary Figure 10 Full, uncropped western images for Extended Data Fig.
Supplementary Figure 11 Full, uncropped western images for Extended Data Fig. Supplementary Table 1 The nutrient panel included in the Biolog screen. Supplementary Table 4 sgRNA sequences used in this study. Supplementary Table 5 qPCR primers used in this study.
Supplementary Table 6 Source data for metabolomics, mouse studies and qPCR. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4. About this article. Cite this article Nwosu, Z. Copy to clipboard. This article is cited by Career pathways, part 13 Alexis A.
Jourdain Feilong Wang Nature Metabolism UPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment Yin Li Manling Jiang Chunlai Lu Nature Communications Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions Owen S.
Skinner Joan Blanco-Fernández Alexis A. Jourdain Nature Metabolism Uridine: as sweet as sugar for some cells? Ward Zeribe C. Nwosu Costas A. Lyssiotis Cell Research Comments By submitting a comment you agree to abide by our Terms and Community Guidelines.
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Lombardi Comprehensive Cancer Center, Georgetown University, Reservoir Road, Washington, DC, , USA. You can also search for this author in PubMed Google Scholar. Correspondence to Claudine Isaacs. Ribose is better known as a sports supplement. However, current evidence indicates that it is not effective for this purpose.
Ribose is not an essential nutrient. Although it is a common sugar present in the bodies of animals and plants, food sources don't supply recommended dosages. Typical doses recommended by sports supplement manufacturers are 1 to 10 g per day. However, researchers have used much higher doses.
For example, in a study focusing on coronary artery disease and exercise-induced ischemia problems with blood supply to the heart , the participants took 15 grams of ribose 4 times a day for 3 days.
Typically provided as a powder to be dissolved in water or in liquid form, ribose is also available commercially in capsules. The dissolved powder has a sweetish taste that some people find unpleasant.
Ribose may be of benefit in improving exercise tolerance in people with angina by helping the heart regenerate its ATP, but the evidence that it works remains highly preliminary.
Sports enthusiasts are more interested in ATP's effects on regular muscles than on the heart muscle. At least one animal study seems to show that skeletal muscle, like heart muscle, replenishes ATP more quickly when ribose is added to the blood.
However, six small double-blind, placebo-controlled trials in humans failed to find any benefit. In one small, double-blind study, ribose failed to prove effective for enhancing mental function.
In a few case reports, ribose apparently has produced an increase in exercise ability in people with a rare condition involving deficiency of the enzyme myoadenylate deaminase AMPD.
Small, double-blind studies have failed to find ribose effective for another rare enzyme deficiency, called McArdle's disease, 10 or for Duchenne's muscular dystrophy.
Individuals with sufficiently severe coronary artery disease suffer reduced blood flow to the heart ischemia with exercise and experience angina pain. One small study examined whether giving ribose can improve exercise tolerance for people with angina. For the next 3 days, the men took either oral ribose 60 mg per day or placebo, after which they repeated the treadmill test.
Results of the final test showed that those taking ribose increased the time they were able to walk before developing EKG signs of ischemia, while those taking placebo had no such improvement.
This preliminary study was too small to prove anything definitively, but it certainly suggests that further investigation would be worthwhile. Another small placebo-controlled study enrolled people with coronary artery disease and congestive heart failure and found that use of ribose supplements improved objective measures of heart function and also enhanced subjective "quality of life.
There are no reports of lasting or damaging side effects from ribose, but formal safety studies have not yet been conducted. Reported minor side effects include diarrhea, gastrointestinal discomfort, nausea, and headache. Pliml W, von Arnim T, Stablein A, et al.
Effects of ribose on exercise-induced ischaemia in stable coronary artery disease. Zollner N, Reiter S, Gross M, et al. Myoadenylate deaminase deficiency: successful symptomatic therapy by high dose oral administration of ribose. Klin Wochenschr.
Copyright: © Li cacer al. Gluten-free athlete nutrition is caner open access article distributed under Metabolism-boosting tips terms of Creative Commons Attribution License. The biochemical agent Ribose in cancer prevention is present as L preventiion D enantiomers 1. The L-ribose enantiomer Ribose in cancer prevention Onion cutting tools and thus, D-ribose is the primary functional isoform of ribose 2. D-ribose is a highly water-soluble 5-carbon sugar, also known as D-furanose, which is present in different types of RNA molecule, including mRNA, transfer RNA and ribosomal RNA 34. D-ribose was first identified as a physiologically important molecule in humans in ; however, its physiological and pathological roles in humans, and in particular in diseases, are still being studied 5.
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