Serine and one-carbon metabolism in cancer (original) (raw)

• Phillips, M. M., Sheaff, M. T. & Szlosarek, P. W. Targeting arginine-dependent cancers with arginine-degrading enzymes: opportunities and challenges. Cancer Res. Treat. 45, 251–262 (2013).
  Article PubMed PubMed Central Google Scholar
• Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer https://dx.doi.org/10.1038/nrc.2016.71 (2016).
• Maddocks, O. D. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013). This paper describes how the tumour suppressor p53 helps cells to adapt to serine starvation, and a therapeutic benefit of dietary depletion of serine in a mouse xenograft model.
  Article CAS PubMed Google Scholar
• Kalhan, S. C. & Hanson, R. W. Resurgence of serine: an often neglected but indispensable amino acid. J. Biol. Chem. 287, 19786–19791 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Furuya, S. An essential role for de novo biosynthesis of l-serine in CNS development. Asia Pac. J. Clin. Nutr. 17 (Suppl. 1), 312–315 (2008).
  CAS PubMed Google Scholar
• De Koning, T. J. & Klomp, L. W. Serine-deficiency syndromes. Curr. Opin. Neurol. 17, 197–204 (2004).
  Article CAS PubMed Google Scholar
• Yoshida, K. et al. Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality. J. Biol. Chem. 279, 3573–3577 (2004).
  Article CAS PubMed Google Scholar
• Jaeken, J. et al. 3-Phosphoglycerate dehydrogenase deficiency and 3-phosphoserine phosphatase deficiency: inborn errors of serine biosynthesis. J. Inherit. Metab. Dis. 19, 223–226 (1996).
  Article CAS PubMed Google Scholar
• Hart, C. E. et al. Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am. J. Hum. Genet. 80, 931–937 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012). A large-scale analysis of nutrient uptake in cancer cells shows avid consumption of serine and demonstrates a role for folate cycle enzymes in cancer development.
  Article CAS PubMed PubMed Central Google Scholar
• Kalhan, S. C. et al. Metabolic and genomic response to dietary isocaloric protein restriction in the rat. J. Biol. Chem. 286, 5266–5277 (2011).
  Article CAS PubMed Google Scholar
• Sun, L. et al. cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Res. 25, 429–444 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Chaneton, B. et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458–462 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ye, J. et al. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc. Natl Acad. Sci. USA 109, 6904–6909 (2012). References 13 and 14 describe the consequences of decreased intracellular serine in the inhibition of PKM2 and promotion of the SSP.
  Article PubMed PubMed Central Google Scholar
• Hitosugi, T. et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell 22, 585–600 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Kung, C. et al. Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem. Biol. 19, 1187–1198 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Davis, S. R. et al. Tracer-derived total and folate-dependent homocysteine remethylation and synthesis rates in humans indicate that serine is the main one-carbon donor. Am. J. Physiol. Endocrinol. Metab. 286, E272–E279 (2004).
  Article CAS PubMed Google Scholar
• Allen, R. W. & Moskowitz, M. Arrest of cell growth in the G1 phase of the cell cycle by serine deprivation. Exp. Cell Res. 116, 127–137 (1978).
  Article CAS PubMed Google Scholar
• Rowe, P. B., Sauer, D., Fahey, D., Craig, G. & McCairns, E. One-carbon metabolism in lectin-activated human lymphocytes. Arch. Biochem. Biophys. 236, 277–288 (1985).
  Article CAS PubMed Google Scholar
• Brosnan, M. E., MacMillan, L., Stevens, J. R. & Brosnan, J. T. Division of labour: how does folate metabolism partition between one-carbon metabolism and amino acid oxidation? Biochem. J. 472, 135–146 (2015).
  Article CAS PubMed Google Scholar
• Tibbetts, A. S. & Appling, D. R. Compartmentalization of mammalian folate-mediated one-carbon metabolism. Annu. Rev. Nutr. 30, 57–81 (2010). An authoritative review of the compartmentalization of the reactions in one-carbon metabolism.
  Article CAS PubMed Google Scholar
• Vazquez, A., Markert, E. K. & Oltvai, Z. N. Serine biosynthesis with one carbon catabolism and the glycine cleavage system represents a novel pathway for ATP generation. PLoS ONE 6, e25881 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Tedeschi, P. M. et al. Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells. Cell Death Dis. 4, e877 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ducker, G. S. et al. Reversal of cytosolic one-carbon flux compensates for loss of the mitochondrial folate pathway. Cell Metab. 23, 1140–1153 (2016). This study shows direct evidence for the plasticity of the folate cycle.
  Article CAS PubMed PubMed Central Google Scholar
• Nikkanen, J. et al. Mitochondrial DNA replication defects disturb cellular dNTP pools and remodel one-carbon metabolism. Cell Metab. 23, 635–648 (2016).
  Article CAS PubMed Google Scholar
• Pasternack, L. B., Laude, D. A. Jr & Appling, D. R. 13C NMR detection of folate-mediated serine and glycine synthesis in vivo in Saccharomyces cerevisiae. Biochemistry 31, 8713–8719 (1992).
  Article CAS PubMed Google Scholar
• Herbig, K. et al. Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses. J. Biol. Chem. 277, 38381–38389 (2002).
  Article CAS PubMed Google Scholar
• Gregory, J. F. 3rd et al. Primed, constant infusion with [2H3]serine allows in vivo kinetic measurement of serine turnover, homocysteine remethylation, and transsulfuration processes in human one-carbon metabolism. Am. J. Clin. Nutr. 72, 1535–1541 (2000).
  Article CAS PubMed Google Scholar
• Fan, J. et al. Quantitative flux analysis reveals folate-dependent NADPH production. Nature 510, 298–302 (2014). This study provides evidence that in some cells, one-carbon metabolism can be an important source of NADPH.
  Article CAS PubMed PubMed Central Google Scholar
• Tucker, E. J. et al. Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Cell Metab. 14, 428–434 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Nilsson, R. et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat. Commun. 5, 3128 (2014).
  Article CAS PubMed Google Scholar
• Lewis, C. A. et al. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol. Cell 55, 253–263 (2014). An elegant use of mutant forms of IDH to analyse the compartmentalization of NADPH production.
  Article CAS PubMed PubMed Central Google Scholar
• Zhao, H., French, J. B., Fang, Y. & Benkovic, S. J. The purinosome, a multi-protein complex involved in the de novo biosynthesis of purines in humans. Chem. Commun. (Camb.) 49, 4444–4452 (2013).
  Article CAS Google Scholar
• Chan, C. Y. et al. Purinosome formation as a function of the cell cycle. Proc. Natl Acad. Sci. USA 112, 1368–1373 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• French, J. B. et al. Spatial colocalization and functional link of purinosomes with mitochondria. Science 351, 733–737 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Girgis, S. et al. Molecular cloning, characterization and alternative splicing of the human cytoplasmic serine hydroxymethyltransferase gene. Gene 210, 315–324 (1998).
  Article CAS PubMed Google Scholar
• Suh, J. R., Herbig, A. K. & Stover, P. J. New perspectives on folate catabolism. Annu. Rev. Nutr. 21, 255–282 (2001).
  Article CAS PubMed Google Scholar
• Field, M. S., Kamynina, E. & Stover, P. J. MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability. Biochimie 126, 27–30 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Bao, X. R. et al. Mitochondrial dysfunction remodels one-carbon metabolism in human cells. eLife 5, e10575 (2016).
  Article PubMed PubMed Central Google Scholar
• Stincone, A. et al. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol. Rev. Camb. Philos. Soc. 90, 927–963 (2015).
  Article PubMed Google Scholar
• Liu, L. et al. Malic enzyme tracers reveal hypoxia-induced switch in adipocyte NADPH pathway usage. Nat. Chem. Biol. 12, 345–352 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Bolusani, S. et al. Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate dehydrogenase isozyme expressed in adult tissues. J. Biol. Chem. 286, 5166–5174 (2011).
  Article CAS PubMed Google Scholar
• MacFarlane, A. J. et al. Cytoplasmic serine hydroxymethyltransferase regulates the metabolic partitioning of methylenetetrahydrofolate but is not essential in mice. J. Biol. Chem. 283, 25846–25853 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mejia, N. R. & MacKenzie, R. E. NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase in transformed cells is a mitochondrial enzyme. Biochem. Biophys. Res. Commun. 155, 1–6 (1988).
  Article CAS PubMed Google Scholar
• Krupenko, S. A. & Oleinik, N. V. 10-formyltetrahydrofolate dehydrogenase, one of the major folate enzymes, is down-regulated in tumor tissues and possesses suppressor effects on cancer cells. Cell Growth Differ. 13, 227–236 (2002).
  CAS PubMed Google Scholar
• Anguera, M. C. et al. Regulation of folate-mediated one-carbon metabolism by 10-formyltetrahydrofolate dehydrogenase. J. Biol. Chem. 281, 18335–18342 (2006).
  Article CAS PubMed Google Scholar
• Krupenko, N. I. et al. ALDH1L2 is the mitochondrial homolog of 10-formyltetrahydrofolate dehydrogenase. J. Biol. Chem. 285, 23056–23063 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Sena, L. A. & Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 48, 158–167 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Liou, G. Y. & Storz, P. Reactive oxygen species in cancer. Free Radic. Res. 44, 479–496 (2010).
  Article CAS PubMed Google Scholar
• Piskounova, E. et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186–191 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Porporato, P. E. et al. A mitochondrial switch promotes tumor metastasis. Cell Rep. 8, 754–766 (2014).
  Article CAS PubMed Google Scholar
• Porporato, P. E., Payen, V. L., Baselet, B. & Sonveaux, P. Metabolic changes associated with tumor metastasis, part 2: mitochondria, lipid and amino acid metabolism. Cell. Mol. Life Sci. 73, 1349–1363 (2015).
  Article CAS PubMed Google Scholar
• Subramani, R. et al. Nimbolide inhibits pancreatic cancer growth and metastasis through ROS-mediated apoptosis and inhibition of epithelial-to-mesenchymal transition. Sci. Rep. 6, 19819 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Cheung, E. C. et al. Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine. Genes Dev. 30, 52–63 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931–947 (2013).
  Article CAS PubMed Google Scholar
• Jiang, L. et al. Reductive carboxylation supports redox homeostasis during anchorage-independent growth. Nature 532, 255–258 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Ye, J. et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4, 1406–1417 (2014). This paper describes a physiological role of serine in controlling mitochondrial ROS levels under conditions of hypoxia.
  Article CAS PubMed PubMed Central Google Scholar
• Ost, M. et al. Muscle mitohormesis promotes cellular survival via serine/glycine pathway flux. FASEB J. 29, 1314–1328 (2015).
  Article CAS PubMed Google Scholar
• Mehrmohamadi, M., Liu, X., Shestov, A. A. & Locasale, J. W. Characterization of the usage of the serine metabolic network in human cancer. Cell Rep. 9, 1507–1519 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Struck, A. W., Thompson, M. L., Wong, L. S. & Micklefield, J. S-Adenosyl-methionine-dependent methyltransferases: highly versatile enzymes in biocatalysis, biosynthesis and other biotechnological applications. Chembiochem 13, 2642–2655 (2012).
  Article CAS PubMed Google Scholar
• Kinnaird, A., Zhao, S., Wellen, K. E. & Michelakis, E. D. Metabolic control of epigenetics in cancer. Nat. Rev. Cancer https://dx.doi.org/10.1038/nrc.2016.82 (2016).
• Sunden, S. L., Renduchintala, M. S., Park, E. I., Miklasz, S. D. & Garrow, T. A. Betaine-homocysteine methyltransferase expression in porcine and human tissues and chromosomal localization of the human gene. Arch. Biochem. Biophys. 345, 171–174 (1997).
  Article CAS PubMed Google Scholar
• Scott, J. M. & Weir, D. G. The methyl folate trap. A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid induced exacerbation of subacute combined degeneration in pernicious anaemia. Lancet 2, 337–340 (1981).
  Article CAS PubMed Google Scholar
• Maddocks, O. D., Labuschagne, C. F., Adams, P. D. & Vousden, K. H. Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol. Cell 61, 210–221 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Mentch, S. J. et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22, 861–873 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Hardie, D. G. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 25, 1895–1908 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Ballatori, N. et al. Glutathione dysregulation and the etiology and progression of human diseases. Biol. Chem. 390, 191–214 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hultberg, B. & Hultberg, M. High glutathione turnover in human cell lines revealed by acivicin inhibition of gamma-glutamyltranspeptidase and the effects of thiol-reactive metals during acivicin inhibition. Clin. Chim. Acta 349, 45–52 (2004).
  Article CAS PubMed Google Scholar
• DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015). A link between oxidative stress and activation of the SSP through NRF2 and ATF4.
  Article CAS PubMed PubMed Central Google Scholar
• Gruning, N. M. et al. Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells. Cell Metab. 14, 415–427 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278–1283 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Snell, K. Enzymes of serine metabolism in normal, developing and neoplastic rat tissues. Adv. Enzyme Regul. 22, 325–400 (1984).
  Article CAS PubMed Google Scholar
• Snell, K., Natsumeda, Y., Eble, J. N., Glover, J. L. & Weber, G. Enzymic imbalance in serine metabolism in human colon carcinoma and rat sarcoma. Br. J. Cancer 57, 87–90 (1988).
  Article CAS PubMed PubMed Central Google Scholar
• Pollari, S. et al. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res. Treat. 125, 421–430 (2011).
  Article CAS PubMed Google Scholar
• Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Mullarky, E., Mattaini, K. R., Vander Heiden, M. G., Cantley, L. C. & Locasale, J. W. PHGDH amplification and altered glucose metabolism in human melanoma. Pigment Cell Melanoma Res. 24, 1112–1115 (2011).
  Article CAS PubMed Google Scholar
• Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat. Genet. 43, 869–874 (2011). References 75–77 show that overexpression of SSP enzymes contributes to the proliferation of some cancers.
  Article CAS PubMed PubMed Central Google Scholar
• Antonov, A. et al. Bioinformatics analysis of the serine and glycine pathway in cancer cells. Oncotarget 5, 11004–11013 (2014).
  Article PubMed PubMed Central Google Scholar
• Pacold, M. E. et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat. Chem. Biol. 12, 452–458 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, J. et al. Phosphoglycerate dehydrogenase induces glioma cells proliferation and invasion by stabilizing forkhead box M1. J. Neurooncol. 111, 245–255 (2013).
  Article CAS PubMed Google Scholar
• Fan, J. et al. Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate. ACS Chem. Biol. 10, 510–516 (2015).
  Article CAS PubMed Google Scholar
• Yoon, S. et al. Clinical implication of serine metabolism-associated enzymes in colon cancer. Oncology 89, 351–359 (2015).
  Article CAS PubMed Google Scholar
• Gylfe, A. E. et al. Eleven candidate susceptibility genes for common familial colorectal cancer. PLoS Genet. 9, e1003876 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Peters, J. M., Shah, Y. M. & Gonzalez, F. J. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat. Rev. Cancer 12, 181–195 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Ericsson, A., Turner, N., Hansson, G. I., Wallenius, K. & Oakes, N. D. Pharmacological PPARα activation markedly alters plasma turnover of the amino acids glycine, serine and arginine in the rat. PLoS ONE 9, e113328 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Nilsson, L. M. et al. Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis. PLoS Genet. 8, e1002573 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Field, M. S. et al. Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency. J. Biol. Chem. 289, 29642–29650 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• MacFarlane, A. J., McEntee, M. F. & Stover, P. J. Azoxymethane-induced colon carcinogenesis in mice occurs independently of de novo thymidylate synthesis capacity. J. Nutr. 144, 419–424 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Macfarlane, A. J., Perry, C. A., McEntee, M. F., Lin, D. M. & Stover, P. J. Shmt1 heterozygosity impairs folate-dependent thymidylate synthesis capacity and modifies risk of Apc(min)-mediated intestinal cancer risk. Cancer Res. 71, 2098–2107 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Anderson, D. D., Woeller, C. F., Chiang, E. P., Shane, B. & Stover, P. J. Serine hydroxymethyltransferase anchors de novo thymidylate synthesis pathway to nuclear lamina for DNA synthesis. J. Biol. Chem. 287, 7051–7062 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Field, M. S., Kamynina, E., Watkins, D., Rosenblatt, D. S. & Stover, P. J. Human mutations in methylenetetrahydrofolate dehydrogenase 1 impair nuclear de novo thymidylate biosynthesis. Proc. Natl Acad. Sci. USA 112, 400–405 (2015).
  Article CAS PubMed Google Scholar
• MacFarlane, A. J., Perry, C. A., McEntee, M. F., Lin, D. M. & Stover, P. J. Mthfd1 is a modifier of chemically induced intestinal carcinogenesis. Carcinogenesis 32, 427–433 (2011).
  Article CAS PubMed Google Scholar
• Lee, G. Y. et al. Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes. Cancer Res. 74, 3114–3126 (2014).
  Article CAS PubMed Google Scholar
• Gustafsson Sheppard, N. et al. The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation. Sci. Rep. 5, 15029 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Lehtinen, L. et al. High-throughput RNAi screening for novel modulators of vimentin expression identifies MTHFD2 as a regulator of breast cancer cell migration and invasion. Oncotarget 4, 48–63 (2013).
  Article PubMed Google Scholar
• Valencia, T. et al. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis. Cancer Cell 26, 121–135 (2014). Inhibition of the SSP in tumour-associated fibroblasts is shown to increase ROS levels, leading to inflammation and enhanced tumour progression.
  Article CAS PubMed PubMed Central Google Scholar
• Bollig-Fischer, A., Dewey, T. G. & Ethier, S. P. Oncogene activation induces metabolic transformation resulting in insulin-independence in human breast cancer cells. PLoS ONE 6, e17959 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Jun, D. Y. et al. Positive regulation of promoter activity of human 3-phosphoglycerate dehydrogenase (PHGDH) gene is mediated by transcription factors Sp1 and NF-Y. Gene 414, 106–114 (2008).
  Article CAS PubMed Google Scholar
• Ding, J. et al. The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. Cell Metab. 18, 896–907 (2013).
  Article CAS PubMed Google Scholar
• Wu, K. C., Cui, J. Y. & Klaassen, C. D. Beneficial role of Nrf2 in regulating NADPH generation and consumption. Toxicol. Sci. 123, 590–600 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Mitsuishi, Y. et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22, 66–79 (2012).
  Article CAS PubMed Google Scholar
• Zhao, E. et al. KDM4C and ATF4 cooperate in transcriptional control of amino acid metabolism. Cell Rep. 14, 506–519 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Berry, W. L. & Janknecht, R. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res. 73, 2936–2942 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Riscal, R. et al. Chromatin-bound MDM2 regulates serine metabolism and redox homeostasis independently of p53. Mol. Cell 62, 890–902 (2016).
  Article CAS PubMed Google Scholar
• Moran, D. M. et al. KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol. Cancer Ther. 13, 1611–1624 (2014).
  Article CAS PubMed Google Scholar
• Audet-Walsh, E. et al. The PGC-1α/ERRα axis represses one-carbon metabolism and promotes sensitivity to anti-folate therapy in breast cancer. Cell Rep. 14, 920–931 (2016).
  Article CAS PubMed Google Scholar
• Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J., Asara, J. M. & Manning, B. D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351, 728–733 (2016). This study describes a mechanism by which mTOR signals to increase purine synthesis by activating mitochondrial folate metabolism.
  Article CAS PubMed PubMed Central Google Scholar
• Ma, L. et al. Control of nutrient stress-induced metabolic reprogramming by PKCζ in tumorigenesis. Cell 152, 599–611 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Ou, Y., Wang, S. J., Jiang, L., Zheng, B. & Gu, W. p53 protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation. J. Biol. Chem. 290, 457–466 (2015).
  Article CAS PubMed Google Scholar
• Amelio, I. et al. p73 regulates serine biosynthesis in cancer. Oncogene 33, 5039–5046 (2014).
  Article CAS PubMed Google Scholar
• Melino, G., De Laurenzi, V. & Vousden, K. H. p73: friend or foe in tumorigenesis. Nat. Rev. Cancer 2, 605–615 (2002).
  Article CAS PubMed Google Scholar
• Kruiswijk, F., Labuschagne, C. F. & Vousden, K. H. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 16, 393–405 (2015).
  Article CAS PubMed Google Scholar
• Labuschagne, C. F., van den Broek, N. J., Mackay, G. M., Vousden, K. H. & Maddocks, O. D. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 7, 1248–1258 (2014). An unexpected inability of tumour cells to use glycine to support the one-carbon cycle and purine production.
  Article CAS PubMed Google Scholar
• Zhang, W. C. et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148, 259–272 (2012). A paper describing the importance of glycine cleavage for tumour development.
  Article CAS PubMed Google Scholar
• Kim, D. et al. SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature 520, 363–367 (2015). A study reconciling the observations in references 113 and 114, showing the importance of glycine cleavage for glycine detoxification, rather than contributing to the one-carbon cycle.
  Article CAS PubMed PubMed Central Google Scholar
• Azize, N. A. et al. Mutation analysis of glycine decarboxylase, aminomethyltransferase and glycine cleavage system protein-H genes in 13 unrelated families with glycine encephalopathy. J. Hum. Genet. 59, 593–597 (2014).
  Article CAS PubMed Google Scholar
• Vousden, K. H. & Lu, X. Live or let die: the cell's response to p53. Nat. Rev. Cancer 2, 594–604 (2002).
  Article CAS PubMed Google Scholar
• Start, K. Treating phenylketonuria by a phenylalanine-free diet. Prof. Care Mother Child 8, 109–110 (1998).
  CAS PubMed Google Scholar
• Hayashi, S., Tanaka, T., Naito, J. & Suda, M. Dietary and hormonal regulation of serine synthesis in the rat. J. Biochem. 77, 207–219 (1975).
  Article CAS PubMed Google Scholar
• Gravel, S. P. et al. Serine deprivation enhances antineoplastic activity of biguanides. Cancer Res. 74, 7521–7533 (2014).
  Article CAS PubMed Google Scholar
• Mullarky, E. et al. Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers. Proc. Natl Acad. Sci. USA 113, 1778–1783 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, J. et al. Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth. Oncotarget 4, 2502–2511 (2013).
  PubMed PubMed Central Google Scholar
• Rose, M. L. et al. Dietary glycine prevents the development of liver tumors caused by the peroxisome proliferator WY-14,643. Carcinogenesis 20, 2075–2081 (1999).
  Article CAS PubMed Google Scholar
• Rose, M. L., Madren, J., Bunzendahl, H. & Thurman, R. G. Dietary glycine inhibits the growth of B16 melanoma tumors in mice. Carcinogenesis 20, 793–798 (1999).
  Article CAS PubMed Google Scholar
• Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572–583 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Gonen, N. & Assaraf, Y. G. Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist. Updat. 15, 183–210 (2012).
  Article CAS PubMed Google Scholar
• Longley, D. B., Harkin, D. P. & Johnston, P. G. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330–338 (2003).
  Article CAS PubMed Google Scholar
• Huennekens, F. M. The methotrexate story: a paradigm for development of cancer chemotherapeutic agents. Adv. Enzyme Regul. 34, 397–419 (1994).
  Article CAS PubMed Google Scholar
• Valik, D., Radina, M., Sterba, J. & Vojtesek, B. Homocysteine: exploring its potential as a pharmacodynamic biomarker of antifolate chemotherapy. Pharmacogenomics 5, 1151–1162 (2004).
  Article CAS PubMed Google Scholar
• Dervieux, T., Greenstein, N. & Kremer, J. Pharmacogenomic and metabolic biomarkers in the folate pathway and their association with methotrexate effects during dosage escalation in rheumatoid arthritis. Arthritis Rheum. 54, 3095–3103 (2006).
  Article CAS PubMed Google Scholar
• Chang, C. & Pearce, E. Emerging concepts of T cell metabolism as a target of immunotherapy. Nat. Immunol. 17, 364–368 (2016).
  Article CAS PubMed PubMed Central Google Scholar
• Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).
  CAS PubMed Google Scholar