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Regulation of cancer cell metabolism

Key Points

  • Multiple molecular mechanisms, both intrinsic and extrinsic, converge to alter core cellular metabolism and provide support for the three basic needs of dividing cells: rapid ATP generation to maintain energy status; increased biosynthesis of macromolecules; and tightened maintenance of appropriate cellular redox status. Metabolic changes are a common feature of cancerous tissues, although it is unclear to what extent these metabolic changes are important in low-grade slow growing tumours.

  • The best characterized metabolic phenotype observed in tumour cells is the Warburg effect, which is a shift from ATP generation through oxidative phosphorylation to ATP generation through glycolysis, even under normal oxygen concentrations. This effect is regulated by the PI3K, hypoxia-indicible factor (HIF), p53, MYC and AMP-activated protein kinase (AMPK)–liver kinase B1 (LKB1) pathways.

  • Metabolic adaptation in tumours extends beyond the Warburg effect. It is becoming clear that alterations to metabolism balance the need of the cell for energy with its equally important need for macromolecular building blocks and maintenance of redox balance. To this end, a key molecule produced as a result of altered cancer metabolism is reduced nicotinamide adenine dinucleotide phosphate (NADPH), which functions as a cofactor and provides reducing power in many enzymatic reactions that are crucial for macromolecular biosynthesis. NADPH is also an antioxidant and forms part of the defence against reactive oxygen species (ROS) that are produced during rapid proliferation.

  • High levels of ROS can cause damage to macromolecules, which can induce senescence and apoptosis. Cells counteract the detrimental effects of ROS by producing antioxidant molecules, such as reduced glutathione (GSH) and thioredoxin (TRX). Several of these antioxidant systems, including GSH and TRX, rely on the reducing power of NADPH to maintain their activities.

  • In addition to the genetic changes that alter tumour cell metabolism, the abnormal tumour microenvironment — such as hypoxia, pH and low glucose concentrations — have a major role in determining the metabolic phenotype of tumour cells.

  • Mutations in oncogenes and tumour suppressor genes cause alterations to multiple intracellular signalling pathways that affect tumour cell metabolism and re-engineer it to allow enhanced survival and growth.

Abstract

Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

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Figure 1: Determinants of the tumour metabolic phenotype.
Figure 2: Molecular mechanisms driving the Warburg effect.
Figure 3: PKM2 and its effect on glycolysis and the pentose phosphate pathway.
Figure 4: Mechanisms of redox control and their alterations in cancer.
Figure 5: IDH1 and IDH2 mutations cause an oncometabolic gain of function.
Figure 6: Relationship between the levels of ROS and cancer.

References

  1. Stratton, M. R., Campbell, P. J. & Futreal, P. A. The cancer genome. Nature 458, 719–724 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. The International Cancer Genome Consortium. International network of cancer genome projects. Nature 464, 993–998 (2010).

  3. Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008). Sequencing of the glioblastoma genome in which mutation of IDH1 was identified as a driver mutation.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009). Provocative review advancing the concept that glycolytic metabolism supports biosynthetic pathways.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Newsholme, E. A., Crabtree, B. & Ardawi, M. S. The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells. Biosci. Rep. 5, 393–400 (1985).

    CAS  PubMed  Article  Google Scholar 

  6. Tatum, J. L. et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int. J. Radiat. Biol. 82, 699–757 (2006).

    CAS  PubMed  Article  Google Scholar 

  7. Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    CAS  PubMed  Article  Google Scholar 

  8. Semenza, G. L. et al. 'The metabolism of tumours': 70 years later. Novartis Found. Symp. 240, 251–260; discussion 260–254 (2001).

    CAS  PubMed  Google Scholar 

  9. Frezza, C. & Gottlieb, E. Mitochondria in cancer: not just innocent bystanders. Semin. Cancer Biol. 19, 4–11 (2009).

    CAS  PubMed  Article  Google Scholar 

  10. Weinhouse, S. The Warburg hypothesis fifty years later. Z. Krebsforsch. Klin. Onkol. Cancer Res. Clin. Oncol. 87, 115–126 (1976).

    CAS  Google Scholar 

  11. Funes, J. M. et al. Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production. Proc. Natl Acad. Sci. USA 104, 6223–6228 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Fogal, V. et al. Mitochondrial p32 protein is a critical regulator of tumor metabolism via maintenance of oxidative phosphorylation. Mol. Cell. Biol. 30, 1303–1318 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Gatenby, R. A. & Gillies, R. J. Why do cancers have high aerobic glycolysis? Nature Rev. Cancer 4, 891–899 (2004).

    CAS  Article  Google Scholar 

  15. Gillies, R. J., Robey, I. & Gatenby, R. A. Causes and consequences of increased glucose metabolism of cancers. J. Nucl. Med. 49 (Suppl. 2), 24S-42S (2008).

  16. Gambhir, S. S. Molecular imaging of cancer with positron emission tomography. Nature Rev. Cancer 2, 683–693 (2002).

    CAS  Article  Google Scholar 

  17. Gambhir, S. S. et al. A tabulated summary of the FDG PET literature. J. Nucl. Med. 42, 1S–93S (2001).

  18. Jadvar, H., Alavi, A. & Gambhir, S. S. 18F-FDG uptake in lung, breast, and colon cancers: molecular biology correlates and disease characterization. J. Nucl. Med. 50, 1820–1827 (2009).

    PubMed  Article  Google Scholar 

  19. Czernin, J. & Phelps, M. E. Positron emission tomography scanning: current and future applications. Annu. Rev. Med. 53, 89–112 (2002).

    CAS  PubMed  Article  Google Scholar 

  20. Le, A. et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc. Natl Acad. Sci. USA 107, 2037–2042 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Fantin, V. R., St-Pierre, J. & Leder, P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9, 425–434 (2006).

    CAS  PubMed  Article  Google Scholar 

  22. Wong, K. K., Engelman, J. A. & Cantley, L. C. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev. 20, 87–90 (2010).

    CAS  PubMed  Article  Google Scholar 

  23. Plas, D. R. & Thompson, C. B. Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24, 7435–7442 (2005).

    CAS  PubMed  Article  Google Scholar 

  24. Elstrom, R. L. et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 64, 3892–3899 (2004).

    CAS  PubMed  Article  Google Scholar 

  25. Fan, Y., Dickman, K. G. & Zong, W. X. Akt and c-Myc differentially activate cellular metabolic programs and prime cells to bioenergetic inhibition. J. Biol. Chem. 285, 7324–7333 (2010).

    CAS  PubMed  Article  Google Scholar 

  26. Robey, R. B. & Hay, N. Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin. Cancer Biol. 19, 25–31 (2009).

    CAS  PubMed  Article  Google Scholar 

  27. Khatri, S., Yepiskoposyan, H., Gallo, C. A., Tandon, P. & Plas, D. R. FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. J. Biol. Chem. 285, 15960–15965 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Fang, M. et al. The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell 143, 711–724 (2010).

    CAS  PubMed  Article  Google Scholar 

  29. Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).

    CAS  PubMed  Article  Google Scholar 

  30. Bertout, J. A., Patel, S. A. & Simon, M. C. The impact of O2 availability on human cancer. Nature Rev. Cancer 8, 967–975 (2008).

    CAS  Article  Google Scholar 

  31. Inoki, K., Corradetti, M. N. & Guan, K. L. Dysregulation of the TSC-mTOR pathway in human disease. Nature Genet. 37, 19–24 (2005).

    CAS  PubMed  Article  Google Scholar 

  32. Kapitsinou, P. P. & Haase, V. H. The VHL tumor suppressor and HIF: insights from genetic studies in mice. Cell Death Differ. 15, 650–659 (2008).

    CAS  PubMed  Article  Google Scholar 

  33. Kaelin, W. G. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nature Rev. Cancer 8, 865–873 (2008).

    CAS  Article  Google Scholar 

  34. Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).

    CAS  PubMed  Article  Google Scholar 

  35. King, A., Selak, M. A. & Gottlieb, E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25, 4675–4682 (2006).

    CAS  PubMed  Article  Google Scholar 

  36. Semenza, G. L. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56 (2010).

    CAS  PubMed  Article  Google Scholar 

  37. Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 (2006).

    CAS  PubMed  Article  Google Scholar 

  38. Kim, J. W., Tchernyshyov, I., Semenza, G. L. & Dang, C. V. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185 (2006). References 37 and 38 showed that HIF1 induces expression of PDK1, which limits the flow of pyruvate into the TCA cycle and decreases oxidative phosphorylation.

    PubMed  Article  CAS  Google Scholar 

  39. Lu, C. W., Lin, S. C., Chen, K. F., Lai, Y. Y. & Tsai, S. J. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J. Biol. Chem. 283, 28106–28114 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Cairns, R. A. et al. Pharmacologically increased tumor hypoxia can be measured by 18F-Fluoroazomycin arabinoside positron emission tomography and enhances tumor response to hypoxic cytotoxin PR-104. Clin. Cancer Res. 15, 7170–7174 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Michelakis, E. D., Webster, L. & Mackey, J. R. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer 99, 989–994 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Semenza, G. L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2010).

    CAS  PubMed  Article  Google Scholar 

  43. Onnis, B., Rapisarda, A. & Melillo, G. Development of HIF-1 inhibitors for cancer therapy. J. Cell. Mol. Med. 13, 2780–2786 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Dang, C. V., Le, A. & Gao, P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin. Cancer Res. 15, 6479–6483 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Kim, J. W., Gao, P., Liu, Y. C., Semenza, G. L. & Dang, C. V. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell. Biol. 27, 7381–7393 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Dang, C. V., Kim, J. W., Gao, P. & Yustein, J. The interplay between MYC and HIF in cancer. Nature Rev. Cancer 8, 51–56 (2008).

    CAS  Article  Google Scholar 

  47. Li, F. et al. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol. Cell. Biol. 25, 6225–6234 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Kuhajda, F. P. AMP-activated protein kinase and human cancer: cancer metabolism revisited. Int. J. Obes. 32 (Suppl. 4), S36–S41 (2008).

    Article  CAS  Google Scholar 

  49. Shackelford, D. B. & Shaw, R. J. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nature Rev. Cancer 9, 563–575 (2009). A comprehensive review of AMPK and LKB1 in cancer metabolism.

    CAS  Article  Google Scholar 

  50. Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005).

    CAS  PubMed  Article  Google Scholar 

  51. Jenne, D. E. et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nature Genet. 18, 38–43 (1998).

    CAS  PubMed  Article  Google Scholar 

  52. Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007).

    CAS  PubMed  Article  Google Scholar 

  53. Wingo, S. N. et al. Somatic LKB1 mutations promote cervical cancer progression. PLoS ONE 4, e5137 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. Wang, W. & Guan, K. L. AMP-activated protein kinase and cancer. Acta Physiol. 196, 55–63 (2009).

    CAS  Article  Google Scholar 

  55. Libby, G. et al. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32, 1620–1625 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Anisimov, V. N. et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp. Gerontol. 40, 685–693 (2005).

    CAS  PubMed  Article  Google Scholar 

  57. Vousden, K. H. & Ryan, K. M. p53 and metabolism. Nature Rev. Cancer 9, 691–700 (2009).

    CAS  Article  Google Scholar 

  58. Mathupala, S. P., Heese, C. & Pedersen, P. L. Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J. Biol. Chem. 272, 22776–22780 (1997).

    CAS  PubMed  Article  Google Scholar 

  59. Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006).

    CAS  PubMed  Article  Google Scholar 

  60. Stambolic, V. et al. Regulation of PTEN transcription by p53. Mol. Cell 8, 317–325 (2001).

    CAS  PubMed  Article  Google Scholar 

  61. Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006).

    CAS  PubMed  Article  Google Scholar 

  62. Almeida, R. et al. OCT-1 is over-expressed in intestinal metaplasia and intestinal gastric carcinomas and binds to, but does not transactivate, CDX2 in gastric cells. J. Pathol. 207, 396–401 (2005).

    CAS  PubMed  Article  Google Scholar 

  63. Jin, T. et al. Examination of POU homeobox gene expression in human breast cancer cells. Int. J. Cancer 81, 104–112 (1999).

    CAS  PubMed  Article  Google Scholar 

  64. Shakya, A. et al. Oct1 loss of function induces a coordinate metabolic shift that opposes tumorigenicity. Nature Cell Biol. 11, 320–327 (2009).

    CAS  PubMed  Article  Google Scholar 

  65. Mazurek, S., Boschek, C. B., Hugo, F. & Eigenbrodt, E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin. Cancer Biol. 15, 300–308 (2005).

    CAS  PubMed  Article  Google Scholar 

  66. Mazurek, S., Zwerschke, W., Jansen-Durr, P. & Eigenbrodt, E. Metabolic cooperation between different oncogenes during cell transformation: interaction between activated ras and HPV-16 E7. Oncogene 20, 6891–6898 (2001).

    CAS  PubMed  Article  Google Scholar 

  67. Zwerschke, W. et al. Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein. Proc. Natl Acad. Sci. USA 96, 1291–1296 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Christofk, H. R., Vander Heiden, M. G., Wu, N., Asara, J. M. & Cantley, L. C. Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452, 181–186 (2008).

    CAS  PubMed  Article  Google Scholar 

  69. Marshall, S., Bacote, V. & Traxinger, R. R. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J. Biol. Chem. 266, 4706–4712 (1991).

    CAS  PubMed  Article  Google Scholar 

  70. Christofk, H. R. et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452, 230–233 (2008). The first mechanistic investigation of PKM2 using experimental cancer models, confirming the hypothesis that PKM2 expression provides an advantage for tumour growth.

    CAS  PubMed  Article  Google Scholar 

  71. David, C. J., Chen, M., Assanah, M., Canoll, P. & Manley, J. L. HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature 463, 364–368 (2009). Discovery and explanation of the connection between the oncoprotein MYC and PKM2 expression.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. Schneider, J. et al. Tumor M2-pyruvate kinase in lung cancer patients: immunohistochemical detection and disease monitoring. Anticancer Res. 22, 311–318 (2002).

    CAS  PubMed  Google Scholar 

  73. Cerwenka, H. et al. TUM2-PK (pyruvate kinase type tumor M2), CA19–19 and CEA in patients with benign, malignant and metastasizing pancreatic lesions. Anticancer Res. 19, 849–851 (1999).

    CAS  PubMed  Google Scholar 

  74. Luftner, D. et al. Tumor type M2 pyruvate kinase expression in advanced breast cancer. Anticancer Res. 20, 5077–5082 (2000).

    CAS  PubMed  Google Scholar 

  75. Nathan, C. & Ding, A. SnapShot: reactive oxygen intermediates (ROI). Cell 140, 951 (2010).

    PubMed  Article  Google Scholar 

  76. Budihardjo, I. I. et al. 6-Aminonicotinamide sensitizes human tumor cell lines to cisplatin. Clin. Cancer Res. 4, 117–130 (1998).

    CAS  PubMed  Google Scholar 

  77. Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Gross, S. et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J. Exp. Med. 207, 339–344 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Zhao, S. et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324, 261–265 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). Discovery that driver mutations in IDH1 cause the acquisition of a novel enzymatic activity and production of 2-HG.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Bleeker, F. E. et al. IDH1 mutations at residue p.R132 (IDH1R132) occur frequently in high-grade gliomas but not in other solid tumors. Hum. Mutat. 30, 7–11 (2009).

    CAS  PubMed  Article  Google Scholar 

  84. Kang, M. R. et al. Mutational analysis of IDH1 codon 132 in glioblastomas and other common cancers. Int. J. Cancer 125, 353–355 (2009).

    CAS  PubMed  Article  Google Scholar 

  85. Giannoni, E., Buricchi, F., Raugei, G., Ramponi, G. & Chiarugi, P. Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage-dependent cell growth. Mol. Cell. Biol. 25, 6391–6403 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Lee, S. R. et al. Reversible inactivation of the tumor suppressor PTEN by H2O2. J. Biol. Chem. 277, 20336–20342 (2002).

    CAS  PubMed  Article  Google Scholar 

  87. Cao, J. et al. Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity. EMBO J. 28, 1505–1517 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Gao, P. et al. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12, 230–238 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Bell, E. L., Emerling, B. M. & Chandel, N. S. Mitochondrial regulation of oxygen sensing. Mitochondrion 5, 322–332 (2005).

    CAS  PubMed  Article  Google Scholar 

  90. Ramsey, M. R. & Sharpless, N. E. ROS as a tumour suppressor? Nature Cell Biol. 8, 1213–1215 (2006).

    CAS  PubMed  Article  Google Scholar 

  91. Takahashi, A. et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nature Cell Biol. 8, 1291–1297 (2006).

    CAS  PubMed  Article  Google Scholar 

  92. Garrido, C. et al. Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 13, 1423–1433 (2006).

    CAS  PubMed  Article  Google Scholar 

  93. Han, D., Antunes, F., Canali, R., Rettori, D. & Cadenas, E. Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J. Biol. Chem. 278, 5557–5563 (2003).

    CAS  PubMed  Article  Google Scholar 

  94. Fruehauf, J. P. & Meyskens, F. L. Reactive oxygen species: a breath of life or death? Clin. Cancer Res. 13, 789–794 (2007).

    CAS  PubMed  Article  Google Scholar 

  95. Bae, Y. S. et al. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J. Biol. Chem. 272, 217–221 (1997).

    CAS  PubMed  Article  Google Scholar 

  96. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. & Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).

    CAS  PubMed  Article  Google Scholar 

  97. Vaughn, A. E. & Deshmukh, M. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nature Cell Biol. 10, 1477–1483 (2008). Evidence that redox control by the GSH system is important in neurons and cancer cells and that reduction of cytochrome c prevents apoptosis.

    CAS  PubMed  Article  Google Scholar 

  98. Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Li, B., Gordon, G. M., Du, C. H., Xu, J. & Du, W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17, 469–480 (2010). Evidence that inappropriate activation of growth and proliferation pathways can lead to excessive stress and cell death.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Ozcan, U. et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29, 541–551 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Nogueira, V. et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14, 458–470 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Liu, Y. et al. MnSOD inhibits proline oxidase-induced apoptosis in colorectal cancer cells. Carcinogenesis 26, 1335–1342 (2005).

    CAS  PubMed  Article  Google Scholar 

  103. Liu, Y., Borchert, G. L., Surazynski, A. & Phang, J. M. Proline oxidase, a p53-induced gene, targets COX-2/PGE2 signaling to induce apoptosis and inhibit tumor growth in colorectal cancers. Oncogene 27, 6729–6737 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Liu, Y. et al. Proline oxidase functions as a mitochondrial tumor suppressor in human cancers. Cancer Res. 69, 6414–6422 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Budanov, A. V., Sablina, A. A., Feinstein, E., Koonin, E. V. & Chumakov, P. M. Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science 304, 596–600 (2004).

    CAS  PubMed  Article  Google Scholar 

  106. Yoon, K. A., Nakamura, Y. & Arakawa, H. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. J. Hum. Genet. 49, 134–140 (2004).

    CAS  PubMed  Article  Google Scholar 

  107. Suzuki, S. et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc. Natl Acad. Sci. USA 107, 7461–7466 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Chen, W. et al. Direct interaction between Nrf2 and p21Cip1/WAF1 upregulates the Nrf2-mediated antioxidant response. Mol. Cell 34, 663–673 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Trachootham, D., Alexandre, J. & Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nature Rev. Drug Discov. 8, 579–591 (2009).

    CAS  Article  Google Scholar 

  110. Trachootham, D. et al. Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism. Blood 112, 1912–1922 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Trachootham, D. et al. Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate. Cancer Cell 10, 241–252 (2006).

    CAS  PubMed  Article  Google Scholar 

  112. Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W. & Ting, J. P. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc. Natl Acad. Sci. USA 103, 15091–15096 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Gasser, T. et al. Genetic complexity and Parkinson's disease. Science 277, 388–389 (1997).

    CAS  PubMed  Google Scholar 

  114. Kim, R. H. et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc. Natl Acad. Sci. USA 102, 5215–5220 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Kim, R. H. et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, 263–273 (2005). Discovery that PARK7 , a gene mutated in Parkinson's disease, is an oncogene.

    CAS  PubMed  Article  Google Scholar 

  116. Davidson, B. et al. Expression and clinical role of DJ-1, a negative regulator of PTEN, in ovarian carcinoma. Hum. Pathol. 39, 87–95 (2008).

    CAS  PubMed  Article  Google Scholar 

  117. Yuen, H. F. et al. DJ-1 could predict worse prognosis in esophageal squamous cell carcinoma. Cancer Epidemiol. Biomarkers Prev. 17, 3593–3602 (2008).

    CAS  PubMed  Article  Google Scholar 

  118. Lin, M. T. & Beal, M. F. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795 (2006).

    CAS  PubMed  Article  Google Scholar 

  119. Bajaj, A., Driver, J. A. & Schernhammer, E. S. Parkinson's disease and cancer risk: a systematic review and meta-analysis. Cancer Causes Control 21, 697–707 (2010).

    PubMed  Article  Google Scholar 

  120. Coles, N. W. & Johnstone, R. M. Glutamine metabolism in Ehrlich ascites-carcinoma cells. Biochem. J. 83, 284–291 (1962).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Reitzer, L. J., Wice, B. M. & Kennell, D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J. Biol. Chem. 254, 2669–2676 (1979).

    CAS  PubMed  Article  Google Scholar 

  122. Eagle, H. Nutrition needs of mammalian cells in tissue culture. Science 122, 501–514 (1955).

    CAS  PubMed  Article  Google Scholar 

  123. Wise, D. R. et al. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc. Natl Acad. Sci. USA 105, 18782–18787 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009). Strong mechanistic evidence that MYC participates in promoting mitochondrial glutaminase activity.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Gallagher, F. A., Kettunen, M. I., Day, S. E., Lerche, M. & Brindle, K. M. 13C MR spectroscopy measurements of glutaminase activity in human hepatocellular carcinoma cells using hyperpolarized 13C-labeled glutamine. Magn. Reson. Med. 60, 253–257 (2008).

    CAS  PubMed  Article  Google Scholar 

  127. Richards, N. G. & Kilberg, M. S. Asparagine synthetase chemotherapy. Annu. Rev. Biochem. 75, 629–654 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Reinert, R. B. et al. Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-asparaginase. J. Biol. Chem. 281, 31222–31233 (2006).

    CAS  PubMed  Article  Google Scholar 

  129. Lunt, S. J., Chaudary, N. & Hill, R. P. The tumor microenvironment and metastatic disease. Clin. Exp. Metastasis 26, 19–34 (2009).

    PubMed  Article  Google Scholar 

  130. Bristow, R. G. & Hill, R. P. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nature Rev. Cancer 8, 180–192 (2008).

    CAS  Article  Google Scholar 

  131. Semenza, G. L. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin. Cancer Biol. 19, 12–16 (2009).

    CAS  PubMed  Article  Google Scholar 

  132. Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Rev. Cancer 8, 705–713 (2008).

    CAS  Article  Google Scholar 

  133. Wouters, B. G. & Koritzinsky, M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nature Rev. Cancer 8, 851–864 (2008).

    CAS  Article  Google Scholar 

  134. Koritzinsky, M. et al. Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J. 25, 1114–1125 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. Rouschop, K. M. & Wouters, B. G. Regulation of autophagy through multiple independent hypoxic signaling pathways. Curr. Mol. Med. 9, 417–424 (2009).

    CAS  PubMed  Article  Google Scholar 

  136. Koumenis, C. et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2α. Mol. Cell. Biol. 22, 7405–7416 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Bi, M. et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 24, 3470–3481 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. Romero-Ramirez, L. et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res. 64, 5943–5947 (2004).

    CAS  PubMed  Article  Google Scholar 

  139. Cairns, R., Papandreou, I. & Denko, N. Overcoming physiologic barriers to cancer treatment by molecularly targeting the tumor microenvironment. Mol. Cancer Res. 4, 61–70 (2006).

    CAS  PubMed  Article  Google Scholar 

  140. Moreno-Sanchez, R., Rodriguez-Enriquez, S., Marin-Hernandez, A. & Saavedra, E. Energy metabolism in tumor cells. FEBS J. 274, 1393–1418 (2007).

    CAS  PubMed  Article  Google Scholar 

  141. Yang, C. et al. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res. 69, 7986–7993 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Sonveaux, P. et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 118, 3930–3942 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to thank M. Saunders for scientific editing of the Review.

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Correspondence to Tak W. Mak.

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DATABASES

National Cancer Institute Drug Dictionary 

L-asparaginase

Pathway Interaction Database 

AMPK

HIF1

HIF2

LKB1

mTOR

MYC

p53

PI3K

FURTHER INFORMATION

Tak W. Mak's homepage

Glossary

Redox status

Balance of the reduced state versus the oxidized state of a biochemical system. This balance is influenced by the level of reactive oxygen and nitrogen species (ROS and RNS) relative to the capacity of antioxidant systems to eliminate ROS and RNS.

Oxidative phosphorylation

Oxygen-dependent process coupling the oxidation of macromolecules and the electron transport chain with ATP synthesis. In eukaryotic cells, it occurs within the mitochondria and is a source of ROS production.

Glycolysis

Oxygen-independent metabolism of glucose and other sugars into pyruvate to produce energy in the form of ATP and intermediate substrates for other metabolic pathways.

Pentose phosphate pathway

PPP. Biochemical pathway converting glucose into substrates for nucleotide biosynthesis and redox control, such as ribose and NADPH. Owing to multiple connections to the glycolytic pathway, the PPP can operate in various modes to allow the production of NADPH and/or ribose as required.

Macromolecular biosynthesis

Biochemical synthesis of the carbohydrates, nucleotides, proteins and lipids that make up cells and tissues. These pathways require energy, reducing power and appropriate substrates.

Reduced nicotinamide adenine dinucleotide phosphate

NADPH. Cofactor that drives anabolic biochemical reactions and provides reducing capacity to combat oxidative stress.

2-hydroxyglutarate

2-HG. A dicarboxylic acid metabolite produced from αKG by the NADPH-dependent reaction of the mutated forms of IDH1 and IDH2. It is also produced at low levels by other enzymes.

Parkinson's disease

A neurodegenerative disorder affecting the CNS, which is characterized by muscle rigidity and the onset of tremors.

Amyotrophic lateral sclerosis

ALS. Also known as Lou Gehrigs disease; it occurs owing to the degeneration of the CNS and leads to the inability to control muscles and eventual muscle atrophy.

Glutaminolysis

The catabolic metabolism of glutamine, which yields substrates that replenish the TCA cycle, produce GSH and supply building blocks for amino acid and nucleotide synthesis.

Anapleurosis

Category of reactions that serve to replenish the intermediate substrates of an anabolic biochemical pathway, especially important in the TCA cycle.

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Cairns, R., Harris, I. & Mak, T. Regulation of cancer cell metabolism. Nat Rev Cancer 11, 85–95 (2011). https://doi.org/10.1038/nrc2981

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