Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Metabolic targets for cancer therapy

Nature Reviews Drug Discovery volume 12, pages 829–846 (2013)Cite this article

Subjects

A Corrigendum to this article was published on 29 November 2013

This article has been updated

Key Points

  • During the past decade, the metabolic alterations that intimately accompany oncogenesis and tumour progression have been intensively investigated, generating great expectations on the development of novel antineoplastic agents that would selectively target the metabolism of malignant cells.

  • With the notable exception of oncometabolites, the metabolism of cancer cells resembles very much that of any rapidly proliferating cell, exhibiting a prominent shift towards anabolic reactions and an increased dependency on intermediates and pathways that — directly or indirectly — sustain such an accelerated biosynthetic activity.

  • At least in some settings, systemic metabolism exerts a prominent influence on carcinogenesis and tumour progression. This is best exemplified by the increased risk of developing cancer that accompanies metabolic syndromes such as diabetes and obesity as well as by the antineoplastic effects of several drugs that are currently used for the treatment of these conditions.

  • The extensive metabolic rewiring of malignant cells is not yet another hallmark of cancer but instead a process that intervenes along with — and hence cannot be discriminated from — oncogenesis. In line with this notion, multiple oncogenes (for example, MYC) and oncosuppressor genes (for example, the tumour suppressor p53 gene TP53) have been shown to regulate bioenergetic and anabolic metabolic circuitries.

  • The accumulation of metabolic intermediates such as fumarate, succinate and 2-hydroxyglutarate suffices to drive oncogenesis, at least in some settings. The existence of such oncometabolites reinforces the notion that the metabolic rearrangements of malignant cells are not a mere epiphenomenon of oncogenesis but one of its crucial components.

  • A huge amount of preclinical data and accumulating clinical experience indicate that several metabolic circuitries can be efficiently targeted to achieve antineoplastic effects in vivo. Thus, in spite of an essential similarity between the metabolism of cancer cells and that of any highly proliferating cell, a therapeutic window exists for this promising approach to treat cancer.

Abstract

Malignant cells exhibit metabolic changes, when compared to their normal counterparts, owing to both genetic and epigenetic alterations. Although such a metabolic rewiring has recently been indicated as yet another general hallmark of cancer, accumulating evidence suggests that the metabolic alterations of each neoplasm represent a molecular signature that intimately accompanies and allows for different facets of malignant transformation. During the past decade, targeting cancer metabolism has emerged as a promising strategy for the development of selective antineoplastic agents. Here, we discuss the intimate relationship between metabolism and malignancy, focusing on strategies through which this central aspect of tumour biology might be turned into cancer's Achilles heel.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Metabolic alterations of cancer cells.
Figure 2: Metabolic targets for cancer therapy.

Change history

  • 29 November 2013

    There were some inaccuracies in a sentence on p839 of the article. The correct sentence is as follows: "Along similar lines, the pharmacological or genetic inhibition of phosphoglycerate mutase 1 (PGAM1) reduces tumour growth in vitro and in vivo, perhaps owing (at least in part) to the PPP-inhibitory effects of 3-phosphoglycerate222. That said, genetic defects that have an impact on the enzymatic activity of G6PD (and hence inhibit the PPP) are common among individuals living in geographical areas with a history of endemic malaria223". This has now been corrected in the online version of the article.

References

  1. Warburg, O. Über den stoffwechsel der carcinomzelle. Biochem. Zeitschr 152, 309–344 (1924).

    CAS  Google Scholar 

  2. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg's contributions to current concepts of cancer metabolism. Nature Rev. Cancer 11, 325–337 (2011).

    Article  CAS  Google Scholar 

  3. Ben-Haim, S. & Ell, P. 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J. Nucl. Med. 50, 88–99 (2009).

    Article  PubMed  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schulze, A. & Harris, A. L. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 491, 364–373 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nature Rev. Cancer 12, 401–410 (2012). This review provides an extensive discussion on the context-dependent role of autophagy in oncogenesis, tumour progression and response to therapy.

    Article  CAS  Google Scholar 

  7. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Vander Heiden, M. G. Targeting cancer metabolism: a therapeutic window opens. Nature Rev. Drug Discov. 10, 671–684 (2011).

    Article  CAS  Google Scholar 

  10. Tennant, D. A., Duran, R. V. & Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nature Rev. Cancer 10, 267–277 (2010).

    Article  CAS  Google Scholar 

  11. Chabner, B. A. & Roberts, T. G. Jr. Timeline: chemotherapy and the war on cancer. Nature Rev. Cancer 5, 65–72 (2005).

    Article  CAS  Google Scholar 

  12. Khandekar, M. J., Cohen, P. & Spiegelman, B. M. Molecular mechanisms of cancer development in obesity. Nature Rev. Cancer 11, 886–895 (2011).

    Article  CAS  Google Scholar 

  13. Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nature Rev. Cancer 12, 159–169 (2012).

    Article  CAS  Google Scholar 

  14. Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R. & Morris, A. D. Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304–1305 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Li, D., Yeung, S. C., Hassan, M. M., Konopleva, M. & Abbruzzese, J. L. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 137, 482–488 (2009).

    Article  PubMed  Google Scholar 

  16. Nielsen, S. F., Nordestgaard, B. G. & Bojesen, S. E. Statin use and reduced cancer-related mortality. N. Engl. J. Med. 367, 1792–1802 (2012). The results of this large, retrospective clinical study suggest that the use of statins by patients with 13 distinct tumour types is associated with a statistically significant reduction in cancer-related mortality.

    Article  CAS  PubMed  Google Scholar 

  17. Poynter, J. N. et al. Statins and the risk of colorectal cancer. N. Engl. J. Med. 352, 2184–2192 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Appleyard, M. V. et al. Phenformin as prophylaxis and therapy in breast cancer xenografts. Br. J. Cancer 106, 1117–1122 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Anisimov, V. N. et al. Central and peripheral effects of insulin/IGF-1 signaling in aging and cancer: antidiabetic drugs as geroprotectors and anticarcinogens. Ann. NY Acad. Sci. 1057, 220–234 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Shackelford, D. B. et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143–158 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Garber, A. J. Metformin: mechanisms of antihyperglycemic action, other pharmacodynamic properties, and safety perspectives. Endocr. Pract. Endocrinol. 3, 359–370 (1997).

    Article  CAS  Google Scholar 

  22. Golomb, B. A. & Evans, M. A. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am. J. Cardiovasc. Drugs 8, 373–418 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Foretz, M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355–2369 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bowker, S. L., Majumdar, S. R., Veugelers, P. & Johnson, J. A. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 29, 254–258 (2006).

    Article  PubMed  Google Scholar 

  25. Hirsch, H. A., Iliopoulos, D. & Struhl, K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc. Natl Acad. Sci. USA 110, 972–977 (2013).

    Article  PubMed  Google Scholar 

  26. Buzzai, M. et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745–6752 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N. & Struhl, K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69, 7507–7511 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fendt, S. M. et al. Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res. 73, 4429–4438 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhuang, L., Kim, J., Adam, R. M., Solomon, K. R. & Freeman, M. R. Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. J. Clin. Invest. 115, 959–968 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ma, L., Niknejad, N., Gorn-Hondermann, I., Dayekh, K. & Dimitroulakos, J. Lovastatin induces multiple stress pathways including LKB1/AMPK activation that regulate its cytotoxic effects in squamous cell carcinoma cells. PloS ONE 7, e46055 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bonovas, S., Nikolopoulos, G. K. & Bagos, P. G. Use of fibrates and cancer risk: a systematic review and meta-analysis of 17 long-term randomized placebo-controlled trials. PloS ONE 7, e45259 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nature Rev. Cancer 13, 227–232 (2013).

    Article  CAS  Google Scholar 

  33. Lee, C. & Longo, V. D. Fasting versus dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene 30, 3305–3316 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Poff, A. M., Ari, C., Seyfried, T. N. & D'Agostino, D. P. The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PloS ONE 8, e65522 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee, C. et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 4, 124ra127 (2012). This study suggested that several cycles of organismal fasting specifically sensitize malignant cells to the antineoplastic effects of several chemotherapeutics.

    Article  Google Scholar 

  36. Couzin, J. Cancer research. Can fasting blunt chemotherapy's debilitating side effects? Science 321, 1146–1147 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Zhou, X. et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142, 531–543 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Kalaany, N. Y. & Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liao, X. et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N. Engl. J. Med. 367, 1596–1606 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sandler, R. S. et al. A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N. Engl. J. Med. 348, 883–890 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Chan, A. T., Ogino, S. & Fuchs, C. S. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N. Engl. J. Med. 356, 2131–2142 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Nishihara, R. et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA 309, 2563–2571 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hawley, S. A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918–922 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nature Rev. Cancer 11, 85–95 (2011).

    Article  CAS  Google Scholar 

  45. Levine, A. J. & Puzio-Kuter, A. M. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330, 1340–1344 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–153 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009). This paper was the first to demonstrate that cancer-associated variants of IDH1 are characterized by a neomorphic enzymatic activity, hence driving the accumulation of the oncometabolite 2-HG.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555–1559 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer 9, 550–562 (2009).

    Article  CAS  Google Scholar 

  56. Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Med. 14, 1351–1356 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Barthel, A. et al. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J. Biol. Chem. 274, 20281–20286 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Samih, N., Hovsepian, S., Aouani, A., Lombardo, D. & Fayet, G. Glut-1 translocation in FRTL-5 thyroid cells: role of phosphatidylinositol 3-kinase and N-glycosylation. Endocrinology 141, 4146–4155 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Clarke, J. F., Young, P. W., Yonezawa, K., Kasuga, M. & Holman, G. D. Inhibition of the translocation of GLUT1 and GLUT4 in 3T3-L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin. Biochem. J. 300, 631–635 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Majewski, N. et al. Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol. Cell 16, 819–830 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Deprez, J., Vertommen, D., Alessi, D. R., Hue, L. & Rider, M. H. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J. Biol. Chem. 272, 17269–17275 (1997).

    Article  CAS  PubMed  Google Scholar 

  62. 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).

    Article  CAS  PubMed  Google Scholar 

  63. Berwick, D. C., Hers, I., Heesom, K. J., Moule, S. K. & Tavare, J. M. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J. Biol. Chem. 277, 33895–33900 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, R. C. et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956–959 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171–183 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Robitaille, A. M. et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339, 1320–1323 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Ben-Sahra, I., Howell, J. J., Asara, J. M. & Manning, B. D. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 339, 1323–1328 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Csibi, A. et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153, 840–854 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ran, C., Liu, H., Hitoshi, Y. & Israel, M. A. Proliferation-independent control of tumor glycolysis by PDGFR-mediated AKT activation. Cancer Res. 73, 1831–1843 (2013).

    Article  CAS  PubMed  Google Scholar 

  72. Zhao, Y. H. et al. Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth. Oncogene 28, 3689–3701 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Youle, R. J. & Strasser, A. The BCL-2 protein family: opposing activities that mediate cell death. Nature Rev. Mol. Cell Biol. 9, 47–59 (2008).

    Article  CAS  Google Scholar 

  74. Rong, Y. & Distelhorst, C. W. Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu. Rev. Physiol. 70, 73–91 (2008).

    Article  CAS  PubMed  Google Scholar 

  75. Alavian, K. N. et al. Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase. Nature Cell Biol. 13, 1224–1233 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Perciavalle, R. M. et al. Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration. Nature Cell Biol. 14, 575–583 (2012). The studies in references 75 and 76 reported that two distinct anti-apoptotic members of the BCL-2 protein family can physically interact with — and hence regulate the enzymatic activity of — the mitochondrial ATP synthase.

    Article  CAS  PubMed  Google Scholar 

  77. Perkins, N. D. The diverse and complex roles of NF-κB subunits in cancer. Nature Rev. Cancer 12, 121–132 (2012).

    Article  CAS  Google Scholar 

  78. Kawauchi, K., Araki, K., Tobiume, K. & Tanaka, N. p53 regulates glucose metabolism through an IKK-NF-κB pathway and inhibits cell transformation. Nature Cell Biol. 10, 611–618 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Watanabe, M., Abe, N., Oshikiri, Y., Stanbridge, E. J. & Kitagawa, T. Selective growth inhibition by glycogen synthase kinase-3 inhibitors in tumorigenic HeLa hybrid cells is mediated through NF-κB-dependent GLUT3 expression. Oncogenesis 1, e21 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Mauro, C. et al. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nature Cell Biol. 13, 1272–1279 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Schwartzenberg-Bar-Yoseph, F., Armoni, M. & Karnieli, E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 64, 2627–2633 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  83. Hu, W. et al. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl Acad. Sci. USA 107, 7455–7460 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  85. Maiuri, M. C. et al. Autophagy regulation by p53. Curr. Opin. Cell Biol. 22, 181–185 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Jiang, P. et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nature Cell Biol. 13, 310–316 (2011).

    Article  CAS  PubMed  Google Scholar 

  87. Morselli, E. et al. p53 inhibits autophagy by interacting with the human ortholog of yeast Atg17, RB1CC1/FIP200. Cell Cycle 10, 2763–2769 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  89. Reid, M. A. et al. The B55α subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Mol. Cell 50, 200–211 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Maddocks, O. D. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013). The studies in references 89 and 90 show that p53 is involved in cytoprotective signal transduction pathways activated by glutamine or serine deprivation, which suggests that p53-deficient malignant cells may be particularly sensitive to chemicals that limit the bioavailability of these amino acids.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  93. Song, M. S., Salmena, L. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor. Nature Rev. Mol. Cell Biol. 13, 283–296 (2012).

    Article  CAS  Google Scholar 

  94. Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391–396 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Tandon, P. et al. Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency. Proc. Natl Acad. Sci. USA 108, 2361–2365 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Garcia-Cao, I. et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell 149, 49–62 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ortega-Molina, A. et al. Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell. Metab. 15, 382–394 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Shackelford, D. B. & Shaw, R. J. The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nature Rev. Cancer 9, 563–575 (2009).

    Article  CAS  Google Scholar 

  99. Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Rev. Mol. Cell Biol. 13, 251–262 (2012).

    Article  CAS  Google Scholar 

  100. Shiloh, Y. & Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature Rev. Mol. Cell Biol. 14, 197–210 (2013).

    Article  CAS  Google Scholar 

  101. Ousset, M. et al. Loss of ATM positively regulates the expression of hypoxia inducible factor 1 (HIF-1) through oxidative stress: role in the physiopathology of the disease. Cell Cycle 9, 2814–2822 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Cam, H., Easton, J. B., High, A. & Houghton, P. J. mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol. Cell 40, 509–520 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Wilson, W. R. & Hay, M. P. Targeting hypoxia in cancer therapy. Nature Rev. Cancer 11, 393–410 (2011).

    Article  CAS  Google Scholar 

  104. Bialik, S. & Kimchi, A. Lethal weapons: DAP-kinase, autophagy and cell death: DAP-kinase regulates autophagy. Curr. Opin. Cell Biol. 22, 199–205 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Mor, I., Carlessi, R., Ast, T., Feinstein, E. & Kimchi, A. Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase. Oncogene 31, 683–693 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Hitosugi, T. et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2, ra73 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. Lv, L. et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth. Mol. Cell 42, 719–730 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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 

  111. Zhong, L. et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell 140, 280–293 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sebastian, C. et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151, 1185–1199 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kaidi, A., Weinert, B. T., Choudhary, C. & Jackson, S. P. Human SIRT6 promotes DNA end resection through CtIP deacetylation. Science 329, 1348–1353 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Min, L. et al. Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin. Nature Cell Biol. 14, 1203–1211 (2012).

    Article  CAS  PubMed  Google Scholar 

  116. Altieri, D. C. Survivin, cancer networks and pathway-directed drug discovery. Nature Rev. Cancer 8, 61–70 (2008).

    Article  CAS  Google Scholar 

  117. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nature Rev. Mol. Cell Biol. 13, 225–238 (2012).

    Article  CAS  Google Scholar 

  118. Saunders, L. R. & Verdin, E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 26, 5489–5504 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Bell, E. L., Emerling, B. M., Ricoult, S. J. & Guarente, L. SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene 30, 2986–2996 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Haigis, M. C., Deng, C. X., Finley, L. W., Kim, H. S. & Gius, D. SIRT3 is a mitochondrial tumor suppressor: a scientific tale that connects aberrant cellular ROS, the Warburg effect, and carcinogenesis. Cancer Res. 72, 2468–2472 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chipuk, J. E. et al. Sphingolipid metabolism cooperates with BAK and BAX to promote the mitochondrial pathway of apoptosis. Cell 148, 988–1000 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gurrieri, C. et al. Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J. Natl Cancer Inst. 96, 269–279 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Carracedo, A. et al. A metabolic prosurvival role for PML in breast cancer. J. Clin. Invest. 122, 3088–3100 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yuan, H. et al. PPARδ induces estrogen receptor-positive mammary neoplasia through an inflammatory and metabolic phenotype linked to mTOR activation. Cancer Res. 73, 4349–4361 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ito, K. et al. A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nature Med. 18, 1350–1358 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Gottlieb, E. & Tomlinson, I. P. Mitochondrial tumour suppressors: a genetic and biochemical update. Nature Rev. Cancer 5, 857–866 (2005).

    Article  CAS  Google Scholar 

  129. Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Letouze, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Owens, K. M. et al. Genomic instability induced by mutant succinate dehydrogenase subunit D (SDHD) is mediated by O2−• and H2O2 . Free Radic. Biol. Med. 52, 160–166 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Dang, L., Jin, S. & Su, S. M. IDH mutations in glioma and acute myeloid leukemia. Trends Mol. Med. 16, 387–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  134. Yang, H., Ye, D., Guan, K. L. & Xiong, Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin. Cancer Res. 18, 5562–5571 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Zhang, W. C. et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148, 259–272 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Sreekumar, A. et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910–914 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Reitman, Z. J. & Yan, H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J. Natl Cancer Inst. 102, 932–941 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Koivunen, P. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484–488 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Leonardi, R., Subramanian, C., Jackowski, S. & Rock, C. O. Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation. J. Biol. Chem. 287, 14615–14620 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Losman, J. A. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621–1625 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2012).

    Article  CAS  Google Scholar 

  149. Mullen, A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385–388 (2012). The studies in references 148 and 149 show that IDH1-catalysed reductive carboxylation is the main metabolic pathway used by malignant cells to divert glutamine towards lipogenesis, especially under hypoxic conditions.

    Article  CAS  Google Scholar 

  150. Gameiro, P. A. et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell. Metab. 17, 372–385 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Fendt, S. M. et al. Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells. Nature Commun. 4, 2236 (2013).

    Article  CAS  Google Scholar 

  152. Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Med. 9, 1269–1274 (2003).

    Article  CAS  PubMed  Google Scholar 

  154. Dwarakanath, B. S. et al. Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: present status and future prospects. J. Cancer Res. Ther. 5 (Suppl. 1), 21–26 (2009).

    Article  CAS  Google Scholar 

  155. Wolf, A. et al. Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. J. Exp. Med. 208, 313–326 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Goldin, N. et al. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene 27, 4636–4643 (2008).

    Article  CAS  PubMed  Google Scholar 

  157. Jae, H. J. et al. The antitumor effect and hepatotoxicity of a hexokinase II inhibitor 3-bromopyruvate: in vivo investigation of intraarterial administration in a rabbit VX2 hepatoma model. Kor. J. Radiol. 10, 596–603 (2009).

    Article  Google Scholar 

  158. Klippel, S. et al. Methyljasmonate displays in vitro and in vivo activity against multiple myeloma cells. Br. J. Haematol. 159, 340–351 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Birsoy, K. et al. MCT1-mediated transport of a toxic molecule is an effective strategy for targeting glycolytic tumors. Nature Genet. 45, 104–108 (2013).

    Article  CAS  PubMed  Google Scholar 

  160. Shoshan, M. C. 3-bromopyruvate: targets and outcomes. J. Bioenerg. Biomembr. 44, 7–15 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Hamanaka, R. B. & Chandel, N. S. Targeting glucose metabolism for cancer therapy. J. Exp. Med. 209, 211–215 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Clem, B. et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Mol. Cancer Ther. 7, 110–120 (2008).

    Article  CAS  PubMed  Google Scholar 

  163. Telang, S. et al. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 25, 7225–7234 (2006).

    Article  CAS  PubMed  Google Scholar 

  164. Clem, B. F. et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol. Cancer Ther. 12, 1461–1470 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Kumagai, S., Narasaki, R. & Hasumi, K. Glucose-dependent active ATP depletion by koningic acid kills high-glycolytic cells. Biochem. Biophys. Res. Commun. 365, 362–368 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Goldberg, M. S. & Sharp, P. A. Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J. Exp. Med. 209, 217–224 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Shim, H. et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl Acad. Sci. USA 94, 6658–6663 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Gautier, E. L. et al. HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders. J. Exp. Med. 210, 339–353 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Liu, Y. et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol. Cancer Ther. 11, 1672–1682 (2012).

    Article  CAS  PubMed  Google Scholar 

  171. Zhan, T., Digel, M., Kuch, E. M., Stremmel, W. & Fullekrug, J. Silybin and dehydrosilybin decrease glucose uptake by inhibiting GLUT proteins. J. Cell. Biochem. 112, 849–859 (2011).

    Article  CAS  PubMed  Google Scholar 

  172. Schneiderhan, W. et al. CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models. Gut 58, 1391–1398 (2009).

    Article  CAS  PubMed  Google Scholar 

  173. Hao, J. et al. In vitro and in vivo prostate cancer metastasis and chemoresistance can be modulated by expression of either CD44 or CD147. PloS ONE 7, e40716 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651–663 (2013).

    Article  CAS  PubMed  Google Scholar 

  175. Anastasiou, D. et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nature Chem. Biol. 8, 839–847 (2012).

    Article  CAS  Google Scholar 

  176. 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 

  177. Cortes-Cros, M. et al. M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth. Proc. Natl Acad. Sci. USA 110, 489–494 (2013).

    Article  PubMed  Google Scholar 

  178. Israelsen, W. J. et al. PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell (in the press).

  179. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Hitosugi, T. et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol. Cell 44, 864–877 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. 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).

    Article  CAS  PubMed  Google Scholar 

  182. 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).

    Article  CAS  PubMed  Google Scholar 

  183. Bonnet, S. et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  184. Shen, Y. C. et al. Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. Br. J. Cancer 108, 72–81 (2013).

    Article  CAS  PubMed  Google Scholar 

  185. Kumar, A., Kant, S. & Singh, S. M. Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: implication of altered glucose metabolism, pH homeostasis and cell survival regulation. Chem. Biol. Interact. 199, 29–37 (2012).

    Article  CAS  PubMed  Google Scholar 

  186. Estrella, V. et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 73, 1524–1535 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Calcinotto, A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 72, 2746–2756 (2012).

    Article  PubMed  Google Scholar 

  188. Michelakis, E. D. et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34 (2010). This study reports that DCA is well tolerated by patients with glioblastoma and it can induce functional alterations in the mitochondria of malignant cells, thus confirming the existence of a therapeutic window for the use of metabolic inhibitors in at least a subset of patients with cancer.

    Article  CAS  PubMed  Google Scholar 

  189. Strum, S. B. et al. Case report: sodium dichloroacetate (DCA) inhibition of the “Warburg Effect” in a human cancer patient: complete response in non-Hodgkin's lymphoma after disease progression with rituximab-CHOP. J. Bioenerg. Biomembr. 45, 307–315 (2013).

    Article  CAS  PubMed  Google Scholar 

  190. Neri, D. & Supuran, C. T. Interfering with pH regulation in tumours as a therapeutic strategy. Nature Rev. Drug Discov. 10, 767–777 (2011).

    Article  CAS  Google Scholar 

  191. Haddad, R. I. et al. A phase II clinical and pharmacodynamic study of E7070 in patients with metastatic, recurrent, or refractory squamous cell carcinoma of the head and neck: modulation of retinoblastoma protein phosphorylation by a novel chloroindolyl sulfonamide cell cycle inhibitor. Clin. Cancer Res. 10, 4680–4687 (2004).

    Article  CAS  PubMed  Google Scholar 

  192. Smyth, J. F. et al. Phase II study of E7070 in patients with metastatic melanoma. Ann. Oncol. 16, 158–161 (2005).

    Article  CAS  PubMed  Google Scholar 

  193. Talbot, D. C. et al. A randomized phase II pharmacokinetic and pharmacodynamic study of indisulam as second-line therapy in patients with advanced non-small cell lung cancer. Clin. Cancer Res. 13, 1816–1822 (2007).

    Article  CAS  PubMed  Google Scholar 

  194. Wallace, D. C. Mitochondria and cancer. Nature Rev. Cancer 12, 685–698 (2012).

    Article  CAS  Google Scholar 

  195. Santidrian, A. F. et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J. Clin. Invest. 123, 1068–1081 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Sharma, L. K. et al. Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum. Mol. Genet. 20, 4605–4616 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Wise, D. R. & Thompson, C. B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci. 35, 427–433 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Fulda, S., Galluzzi, L. & Kroemer, G. Targeting mitochondria for cancer therapy. Nature Rev. Drug Discov. 9, 447–464 (2010).

    Article  CAS  Google Scholar 

  200. El-Mir, M. Y. et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223–228 (2000).

    Article  CAS  PubMed  Google Scholar 

  201. Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. 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 

  203. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).

    Article  CAS  PubMed  Google Scholar 

  204. Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013). The studies in references 203 and 204 were the first to demonstrate that small chemicals that specifically target cancer-associated IDH1 and IDH2 variants can limit the proliferation and induce the differentiation of glioma and leukaemia cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Wang, J. B. et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 207–219 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Seltzer, M. J. et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 70, 8981–8987 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Cheng, T. et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc. Natl Acad. Sci. USA 108, 8674–8679 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Enns, G. M. et al. Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N. Engl. J. Med. 356, 2282–2292 (2007).

    Article  CAS  PubMed  Google Scholar 

  210. Chang, S. M. et al. Phase II study of phenylacetate in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report. J. Clin. Oncol. 17, 984–990 (1999).

    Article  CAS  PubMed  Google Scholar 

  211. Camacho, L. H. et al. Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors. Investigat. Drugs 25, 131–138 (2007).

    Article  CAS  Google Scholar 

  212. Carducci, M. A. et al. A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule. Clin. Cancer Res. 7, 3047–3055 (2001).

    CAS  PubMed  Google Scholar 

  213. Pike, L. S., Smift, A. L., Croteau, N. J., Ferrick, D. A. & Wu, M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim. Biophys. Acta 1807, 726–734 (2011).

    Article  CAS  PubMed  Google Scholar 

  214. Samudio, I. et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J. Clin. Invest. 120, 142–156 (2010).

    Article  CAS  PubMed  Google Scholar 

  215. Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Holubarsch, C. J. et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin. Sci. 113, 205–212 (2007).

    Article  CAS  Google Scholar 

  217. Kantor, P. F., Lucien, A., Kozak, R. & Lopaschuk, G. D. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ. Res. 86, 580–588 (2000).

    Article  CAS  PubMed  Google Scholar 

  218. Andela, V. B., Altuwaijri, S., Wood, J. & Rosier, R. N. Inhibition of β-oxidative respiration is a therapeutic window associated with the cancer chemo-preventive activity of PPARγ agonists. FEBS Lett. 579, 1765–1769 (2005).

    Article  CAS  PubMed  Google Scholar 

  219. Suckow, M. A. et al. The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC(Min/+) mice. Cancer Lett. 209, 165–169 (2004).

    Article  CAS  PubMed  Google Scholar 

  220. Kuo, W., Lin, J. & Tang, T. K. Human glucose-6-phosphate dehydrogenase (G6PD) gene transforms NIH 3T3 cells and induces tumors in nude mice. Int. J. Cancer 85, 857–864 (2000).

    Article  CAS  PubMed  Google Scholar 

  221. Yuan, W. et al. Silencing of TKTL1 by siRNA inhibits proliferation of human gastric cancer cells in vitro and in vivo. Cancer Biol. Ther. 9, 710–716 (2010).

    Article  CAS  PubMed  Google Scholar 

  222. 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 

  223. Howes, R. E., Battle, K. E., Satyagraha, A. W., Baird, J. K. & Hay, S. I. G6PD deficiency: global distribution, genetic variants and primaquine therapy. Adv. Parasitol. 81, 133–201 (2013).

    Article  PubMed  Google Scholar 

  224. Pisano, M., Cocco, P., Cherchi, R., Onnis, R. & Cherchi, P. Glucose-6-phosphate dehydrogenase deficiency and lung cancer: a hospital based case-control study. Tumori 77, 12–15 (1991).

    Article  CAS  PubMed  Google Scholar 

  225. Cocco, P., Dessi, S., Avataneo, G., Picchiri, G. & Heinemann, E. Glucose-6-phosphate dehydrogenase deficiency and cancer in a Sardinian male population: a case-control study. Carcinogenesis 10, 813–816 (1989).

    Article  CAS  PubMed  Google Scholar 

  226. 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 

  227. Keller, K. E., Tan, I. S. & Lee, Y. S. SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. Science 338, 1069–1072 (2012). The studies in references 226 and 227 showed that serine and SAICAR operate as endogenous allosteric activators of PKM2, de facto adjusting the glycolytic flux on the anabolic demand of malignant cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genet. 43, 869–874 (2011).

    Article  CAS  PubMed  Google Scholar 

  230. 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 

  231. Broome, J. D. Studies on the mechanism of tumor inhibition by L-asparaginase. Effects of the enzyme on asparagine levels in the blood, normal tissues, and 6C3HED lymphomas of mice: differences in asparagine formation and utilization in asparaginase-sensitive and -resistant lymphoma cells. J. Exp. Med. 127, 1055–1072 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Bach, S. J. & Swaine, D. The effect of arginase on the retardation of tumour growth. Br. J. Cancer 19, 379–386 (1965).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012). Using an extensive metabolomic profiling approach, the authors of this study identified a crucial role for glycine in the elevated proliferation rate of malignant cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Muller, H. J. & Boos, J. Use of L-asparaginase in childhood ALL. Crit. Rev. Oncol. Hematol. 28, 97–113 (1998).

    Article  CAS  PubMed  Google Scholar 

  235. Ott, P. A. et al. Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma. Invest. New Drugs 31, 425–434 (2013).

    Article  CAS  PubMed  Google Scholar 

  236. Yang, T. S. et al. A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients. Br. J. Cancer 103, 954–960 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Sabatini, D. M. mTOR and cancer: insights into a complex relationship. Nature Rev. Cancer 6, 729–734 (2006).

    Article  CAS  Google Scholar 

  238. Benjamin, D., Colombi, M., Moroni, C. & Hall, M. N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nature Rev. Drug Discov. 10, 868–880 (2011).

    Article  CAS  Google Scholar 

  239. Frezza, C. et al. Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PloS ONE 6, e24411 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Rev. Cancer 7, 763–777 (2007).

    Article  CAS  PubMed  Google Scholar 

  241. Alli, P. M., Pinn, M. L., Jaffee, E. M., McFadden, J. M. & Kuhajda, F. P. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 24, 39–46 (2005).

    Article  CAS  PubMed  Google Scholar 

  242. Seguin, F. et al. The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas. Br. J. Cancer 107, 977–987 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Hatzivassiliou, G. et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311–321 (2005).

    Article  CAS  PubMed  Google Scholar 

  244. Beckers, A. et al. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res. 67, 8180–8187 (2007).

    Article  CAS  PubMed  Google Scholar 

  245. Clem, B. F. et al. A novel small molecule antagonist of choline kinase-alpha that simultaneously suppresses MAPK and PI3K/AKT signaling. Oncogene 30, 3370–3380 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Yalcin, A. et al. Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling. Oncogene 29, 139–149 (2010).

    Article  CAS  PubMed  Google Scholar 

  247. Nomura, D. K. et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140, 49–61 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Cao, Z. et al. MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase. Cancer Res. 71, 2286–2297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Kridel, S. J., Axelrod, F., Rozenkrantz, N. & Smith, J. W. Orlistat is a novel inhibitor of fatty acid synthase with antitumor activity. Cancer Res. 64, 2070–2075 (2004).

    Article  CAS  PubMed  Google Scholar 

  250. Ghosh-Choudhury, N., Mandal, C. C., Ghosh-Choudhury, N. & Ghosh Choudhury, G. Simvastatin induces derepression of PTEN expression via NFκB to inhibit breast cancer cell growth. Cell. Signal. 22, 749–758 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Bajrami, I. et al. Synthetic lethality of PARP and NAMPT inhibition in triple-negative breast cancer cells. EMBO Mol. Med. 4, 1087–1096 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Okumura, S., Sasaki, T., Minami, Y. & Ohsaki, Y. Nicotinamide phosphoribosyltransferase: a potent therapeutic target in non-small cell lung cancer with epidermal growth factor receptor-gene mutation. J. Thorac. Oncol. 7, 49–56 (2012).

    Article  CAS  PubMed  Google Scholar 

  253. Holen, K., Saltz, L. B., Hollywood, E., Burk, K. & Hanauske, A. R. The pharmacokinetics, toxicities, and biologic effects of FK866, a nicotinamide adenine dinucleotide biosynthesis inhibitor. Invest. New Drugs 26, 45–51 (2008).

    Article  CAS  PubMed  Google Scholar 

  254. Tibes, R. et al. Results from a phase I, dose-escalation study of PX-478, an orally available inhibitor of HIF-1α. J. Clin. Oncol. 18, Abstr. 3076 (2010).

    Article  Google Scholar 

  255. Sheen, J. H., Zoncu, R., Kim, D. & Sabatini, D. M. Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell 19, 613–628 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Galluzzi, L. et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 19, 107–120 (2012).

    Article  CAS  PubMed  Google Scholar 

  257. Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109–1112 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Ma, Y., Galluzzi, L., Zitvogel, L. & Kroemer, G. Autophagy and cellular immune responses. Immunity 39, 211–227 (2013).

    Article  CAS  PubMed  Google Scholar 

  259. Wellen, K. E. & Thompson, C. B. A two-way street: reciprocal regulation of metabolism and signalling. Nature Rev. Mol. Cell Biol. 13, 270–276 (2012). This article provides compelling arguments in support of the notion that metabolism and signal transduction do not constitute entirely separated entities but are instead intimately interconnected and hence cannot be discriminated from each other.

    Article  CAS  Google Scholar 

  260. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Raj, L. et al. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 475, 231–234 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Li, T. et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269–1283 (2012). This is the first paper to demonstrate that p53 can mediate oncosuppressive functions even in conditions in which it cannot trigger cell cycle blockade, senescence or apoptosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Locasale, J. W. & Cantley, L. C. Metabolic flux and the regulation of mammalian cell growth. Cell. Metab. 14, 443–451 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Galluzzi, L., Kepp, O. & Kroemer, G. Mitochondria: master regulators of danger signalling. Nature Rev. Mol. Cell Biol. 13, 780–788 (2012).

    Article  CAS  Google Scholar 

  266. Galluzzi, L., Kepp, O., Trojel-Hansen, C. & Kroemer, G. Non-apoptotic functions of apoptosis-regulatory proteins. EMBO Rep. 13, 322–330 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Gao, X., Wang, H., Yang, J. J., Liu, X. & Liu, Z. R. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol. Cell 45, 598–609 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Yang, W. et al. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature 480, 118–122 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Luo, W. et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732–744 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Lunt, S. Y. & Vander Heiden, M. G. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441–464 (2011).

    Article  CAS  PubMed  Google Scholar 

  271. Fritz, V. & Fajas, L. Metabolism and proliferation share common regulatory pathways in cancer cells. Oncogene 29, 4369–4377 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Freed-Pastor, W. A. et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148, 244–258 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Munoz-Pinedo, C., El Mjiyad, N. & Ricci, J. E. Cancer metabolism: current perspectives and future directions. Cell Death Dis. 3, e248 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Michalek, R. D. & Rathmell, J. C. The metabolic life and times of a T-cell. Immunol. Rev. 236, 190–202 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Altman, B. J. & Dang, C. V. Normal and cancer cell metabolism: lymphocytes and lymphoma. FEBS J. 279, 2598–2609 (2012).

    Article  CAS  PubMed  Google Scholar 

  276. Yuneva, M. O. et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell. Metab. 15, 157–170 (2012). This study formally demonstrated that the metabolic profile of neoplastic cells depends not only on their genetic background but also on the tissue in which they develop.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Pietras, K. & Ostman, A. Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 316, 1324–1331 (2010).

    Article  CAS  PubMed  Google Scholar 

  278. Nagaraj, S. & Gabrilovich, D. I. Myeloid-derived suppressor cells in human cancer. Cancer J. 16, 348–353 (2010).

    Article  CAS  PubMed  Google Scholar 

  279. Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Med. 17, 1498–1503 (2011). This study was the first to propose that normal adipocytes stimulate tumour progression not only as they release cytokines but also as they directly transfer fatty acid to malignant cells, thus boosting their proliferation.

    Article  CAS  PubMed  Google Scholar 

  280. Whitaker-Menezes, D. et al. Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 10, 1772–1783 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Martinez-Outschoorn, U. E. et al. Cancer cells metabolically “fertilize” the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors. Cell Cycle 10, 2504–2520 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Kasischke, K. A., Vishwasrao, H. D., Fisher, P. J., Zipfel, W. R. & Webb, W. W. Neural activity triggers neuronal oxidative metabolism followed by astrocytic glycolysis. Science 305, 99–103 (2004).

    Article  CAS  PubMed  Google Scholar 

  283. Chiavarina, B. et al. Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth. Cancer Biol. Ther. 12, 1101–1113 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Sotgia, F. et al. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res. 13, 213 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  285. Dai, C., Whitesell, L., Rogers, A. B. & Lindquist, S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130, 1005–1018 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Vander Heiden, M. G. et al. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem. Pharmacol. 79, 1118–1124 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR); AXA Chair for Longevity Research; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).

Author information

Authors and Affiliations

  1. Université Paris Descartes, Sorbonne Paris Cité, Paris, F-75006, France

    Lorenzo Galluzzi, Oliver Kepp & Guido Kroemer

  2. Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, F-75006, France

    Lorenzo Galluzzi, Oliver Kepp & Guido Kroemer

  3. Gustave Roussy, Villejuif, F-94805, France

    Lorenzo Galluzzi & Oliver Kepp

  4. INSERM, U848, Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille Desmoulins, Villejuif, F-94805, France

    Oliver Kepp & Guido Kroemer

  5. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Matthew G. Vander Heiden

  6. Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Matthew G. Vander Heiden

  7. Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, F-94805, France

    Guido Kroemer

  8. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, F-75015, France

    Guido Kroemer

Authors
  1. Lorenzo Galluzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Kepp
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew G. Vander Heiden
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guido Kroemer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guido Kroemer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Supplementary information

Supplementary information S1 (table)

Metabolic targets for cancer therapy (PDF 416 kb)

Glossary

18F-deoxyglucose positron emission tomography

(18FDG–PET). An imaging procedure that is widely used in oncology for diagnostic, staging or monitoring purposes. 18FDG–PET relies on a radioactive glucose analogue that is preferentially taken up and retained by malignant cells in the context of the Warburg effect.

Pentose phosphate pathway

(PPP). A metabolic circuitry (also known as phosphogluconate pathway or hexose monophosphate shunt) that converts glycolytic intermediates (mainly glucose-6-phosphate, fructose-6-phosphate and glyceraldehyde-3-phosphate) into pentoses (5-carbon sugars) and NADPH.

Macroautophagy

An evolutionarily conserved mechanism that targets intracellular components for lysosomal degradation. Macroautophagy has a major role in the maintenance of intracellular homeostasis as well as in the response of cells to adverse microenvironmental conditions, including nutrient deprivation and hypoxia.

Lactate shuttle

A cell-extrinsic metabolic circuitry that is based on the release of glycolytic lactate from one cell type (for example, astrocytes) and its uptake by another cell type (for example, neurons), which uses lactate to fuel oxidative phosphorylation.

Lactic acidosis

A medical condition (also known as metabolic acidosis) that is characterized by a reduction in the pH of tissues and blood, and is often caused by the extracellular accumulation of lactate.

Ketogenic diet

A high-fat, adequate-protein, low-carbohydrate diet that forces an organism to produce energy mostly via fatty acid oxidation rather than via the catabolism of carbohydrates. This is generally associated with an increase in the levels of circulating ketone bodies, which have beneficial effects in some forms of epilepsy.

2-hydroxyglutarate

(2-HG). An oncometabolite originating from the reduction of α-ketoglutarate as catalysed by the neomorphic enzymatic activity associated with specific isocitrate dehydrogenase mutations.

Hexokinase 2

(HK2). A member of an enzyme family that catalyses the essentially irreversible phosphorylation of glucose to glucose-6-phosphate, de facto trapping it in the cytoplasm and rendering it available for metabolic processes including glycolysis or glycogen synthesis.

Anaplerotic conversion

Reaction that contributes to the replenishment of metabolic intermediates involved in a metabolic circuitry but does not pertain to the same circuitry. A classic example of anaplerosis refers to the replenishment of Krebs cycle intermediates via the direct conversion of pyruvate (or aspartate) into oxaloacetate, glutamate into α-ketoglutarate, or adenylosuccinate into fumarate.

Lactate dehydrogenase A

(LDHA). A member of the LDH family. LDH is an abundant cytosolic enzyme that catalyses the reversible conversion of pyruvate and NADH into lactate and NAD+.

Mitochondrial apoptosis

A regulated signal transduction cascade leading to the apoptotic demise of cells upon the permeabilization of mitochondrial membranes, resulting in the functional impairment of mitochondria and in the release of cytotoxic proteins into the cytosol.

Succinate dehydrogenase

(SDH). An enzyme of the inner mitochondrial membrane that catalyses the oxidation of succinate to fumarate, which is coupled to the reduction of ubiquinone to ubiquinol, de facto being simultaneously involved in the Krebs cycle and in mitochondrial respiration.

Fumarate hydratase

(FH). An enzyme that catalyses the reversible hydration of fumarate to malate. The mitochondrial isoenzyme of FH is involved in the Krebs cycle.

Isocitrate dehydrogenase

(IDH). An enzyme that catalyses the reversible oxidative decarboxylation of isocitrate, producing α-ketoglutarate and carbon dioxide. The mitochondrial isoenzyme (IDH2) is involved in the Krebs cycle.

Oncometabolite

A small chemical produced in the context of intermediate metabolism that is sufficient to promote oncogenesis following its accumulation.

Carbonic anhydrase

One of several zinc-containing enzymes that catalyses the reversible conversion of carbon dioxide and water into carbonic acid (H2CO3), which — in physiological conditions — rapidly dissociates into H+ and HCO3−, thus exerting a major pH-regulatory function.

Glutamate dehydrogenase 1

(GLUD1). A mitochondrial enzyme that catalyses the essentially irreversible conversion of α-ketoglutarate into glutamate and ammonia. The reverse (anaplerotic) reaction is highly unfavoured in mammals owing to the very low affinity of GLUD1 for ammonia.

Carnitine shuttle

A multi-enzymatic system that relies on carnitine as a recyclable vehicle for the import of cytosolic fatty acids into the mitochondrial matrix.

Apcmin/+ mice

Mice harbouring a heterozygous mutation that results in the expression of a truncated form of adenomatosis polyposis coli (APC). Owing to this alteration, Apcmin/+ mice can develop up to 100 polyps in the small intestine as well as colorectal tumours.

Auxotrophic

The state of cells or organisms that are unable to synthesize a metabolite that is strictly required for their own survival or growth.

Rapalogue

Any of several chemical agents that resemble rapamycin in its capacity to inhibit the enzymatic activity of mammalian target of rapamycin.

Antimetabolites

Any of several antineoplastic drugs that operate, at least in part, by inhibiting the metabolism of nucleic acids. Several antimetabolites are currently approved for use in patients with cancer.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Galluzzi, L., Kepp, O., Heiden, M. et al. Metabolic targets for cancer therapy. Nat Rev Drug Discov 12, 829–846 (2013). https://doi.org/10.1038/nrd4145

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd4145

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer