Metabolic targets for cancer therapy

Nature Reviews Drug Discovery

Volumn 12, Issue 11, 2013, Pages 829-846

  Galluzzi, Lorenzo ^a,b,c   Kepp, Oliver ^a,b,c,d   Heiden, Matthew G Vander ^e,f   Kroemer, Guido ^a,b,d,g,h  

^a UNIVERSITÉ PARIS DESCARTES   (France)

^b CENTRE DE RECHERCHE DES CORDELIERS   (France)

^c INSTITUT GUSTAVE ROUSSY   (France)

^d Institut Gustave Roussy   (France)

^e MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^f HARVARD MEDICAL SCHOOL   (United States)

^g Metabolomics Platform   (France)

^h HÔPITAL EUROPÉEN GEORGES POMPIDOU   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ACETAZOLAMIDE; ACETYLSALICYLIC ACID; ANTINEOPLASTIC AGENT; ASPARAGINASE; AZD 3965; BROMOPYRUVIC ACID; CARIPORIDE; DAPORINAD; DEOXYGLUCOSE; DICHLOROACETIC ACID; ETOMOXIR; EVEROLIMUS; FIBRIC ACID DERIVATIVE; FLUOROURACIL; GEMCITABINE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INDISULAM; JASMONIC ACID METHYL ESTER; LONIDAMINE; METFORMIN; METHOTREXATE; ONCOENZYME; ONCOPROTEIN; OXYGEN; PEGYLATED ARGININE DEIMINASE; PHENFORMIN; TEMSIROLIMUS; TLN 232; TRIMETAZIDINE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ACUTE LYMPHOBLASTIC LEUKEMIA; AEROBIC METABOLISM; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; AUTOPHAGY; BILE DUCT CARCINOMA; BIOENERGETIC METABOLISM; BIOENERGY; BREAST CANCER; BREAST CARCINOMA; CACHEXIA; CALORIC INTAKE; CANCER CELL; CANCER CELL METABOLISM; CANCER DIAGNOSIS; CANCER MORTALITY; CANCER PROGNOSIS; CANCER RADIOTHERAPY; CANCER RISK; CANCER SURVIVAL; CANCER THERAPY; CARCINOGENESIS; CARDIOVASCULAR DISEASE; CELL ENERGY; CELL METABOLISM; CITRIC ACID CYCLE; COLORECTAL CANCER; CONTINUOUS INFUSION; DIABETES MELLITUS; DRUG ABSORPTION; DRUG APPROVAL; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG DOSE ESCALATION; DRUG INDICATION; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; ENERGY EXPENDITURE; ENZYME ACTIVATION; ENZYME INHIBITION; EPIGENETICS; FATTY ACID OXIDATION; FOLATE METABOLISM; GASTROINTESTINAL SYMPTOM; GENE ACTIVATION; GENE DELETION; GLIOBLASTOMA; GLIOMA; GLUCOSE UTILIZATION; GLYCOLYSIS; HEAD AND NECK CANCER; HUMAN; HYPERBARIC OXYGEN; KETOGENIC DIET; KIDNEY CARCINOMA; KIDNEY METASTASIS; LACTIC ACIDOSIS; LIPOGENESIS; LIVER CELL CARCINOMA; LIVER TOXICITY; LUNG CANCER; LUNG NON SMALL CELL CANCER; MALIGNANT TRANSFORMATION; MELANOMA; METABOLIC DISORDER; METABOLITE; METASTASIS; MITOCHONDRIAL RESPIRATION; MUSCLE ATROPHY; NEOPLASM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; ONCOGENE K RAS; ONCOMETABOLITE; OXIDATIVE PHOSPHORYLATION; OXIDATIVE STRESS; PANCREAS CANCER; PENTOSE PHOSPHATE CYCLE; POINT MUTATION; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; PROMYELOCYTIC LEUKEMIA; PROSTATE CANCER; PROTEIN FUNCTION; PROTEIN INTAKE; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR; STEROIDOGENESIS; THROMBOCYTOPENIA; TUMOR GROWTH; TUMOR MICROENVIRONMENT; UNSPECIFIED SIDE EFFECT; URINARY EXCRETION;

ANTINEOPLASTIC AGENTS; CELL TRANSFORMATION, NEOPLASTIC; HUMANS; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84887045362     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4145     Document Type: Review

References (286)

1. Warburg, O. Über den stoffwechsel der carcinomzelle. Biochem. Zeitschr 152, 309-344 (1924).
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).
3. 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J. Nucl. Med. 50, 88-99 (2009).
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).
5. Schulze, A. & Harris, A. L. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 491, 364-373 (2012).
6. White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nature Rev. Cancer 12, 401-410 (2012).
7. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000).
8. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674 (2011).
9. Vander Heiden, M. G. Targeting cancer metabolism: a therapeutic window opens. Nature Rev. Drug Discov. 10, 671-684 (2011).
10. Tennant, D. A., Duran, R. V. & Gottlieb, E. Targeting metabolic transformation for cancer therapy. Nature Rev. Cancer 10, 267-277 (2010).
11. Chabner, B. A. & Roberts, T. G. Jr. Timeline: chemotherapy and the war on cancer. Nature Rev. Cancer 5, 65-72 (2005).
12. Khandekar, M. J., Cohen, P. & Spiegelman, B. M. Molecular mechanisms of cancer development in obesity. Nature Rev. Cancer 11, 886-895 (2011).
13. Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nature Rev. Cancer 12, 159-169 (2012).
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).
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).
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).
17. Poynter, J. N. et al. Statins and the risk of colorectal cancer. N. Engl. J. Med. 352, 2184-2192 (2005).
18. Appleyard, M. V. et al. Phenformin as prophylaxis and therapy in breast cancer xenografts. Br. J. Cancer 106, 1117-1122 (2012).
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).
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)
21. Garber, A. J. Metformin: mechanisms of antihyperglycemic action, other pharmacodynamic properties, and safety perspectives. Endocr. Pract. Endocrinol. 3, 359-370 (1997).
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).
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).
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).
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 11 0, 972-977 (2013).
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).
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).
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).
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. 11 5, 959-968 (2005).
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).
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).
32. Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nature Rev. Cancer 13, 227-232 (2013).
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).
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).
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).
36. Couzin, J. Cancer research. Can fasting blunt chemotherapy's debilitating side effects? Science 321, 1146-1147 (2008).
37. Zhou, X. et al. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142, 531-543 (2010).
38. Kalaany, N. Y. & Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725-731 (2009).
39. Liao, X. et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N. Engl. J. Med. 367, 1596-1606 (2012).
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).
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).
42. Nishihara, R. et al. Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA 309, 2563-2571 (2013).
43. Hawley, S. A. et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 336, 918-922 (2012).
44. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nature Rev. Cancer 11, 85-95 (2011).
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).
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).
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).
48. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739-744 (2009).
49. Dang, C. V., Le, A. & Gao, P. MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin. Cancer Res. 15, 6479-6483 (2009).
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).
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).
52. Gao, P. et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762-765 (2009).
53. Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555-1559 (2009).
54. Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656-670 (2012).
55. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nature Rev. Cancer 9, 550-562 (2009).
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).
57. Barthel, A. et al. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J. Biol. Chem. 274, 20281-20286 (1999).
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).
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).
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).
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).
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).
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).
64. Wang, R. C. et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956-959 (2012).
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).
66. Duvel, K. et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol. Cell 39, 171-183 (2010).
67. Robitaille, A. M. et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 339, 1320-1323 (2013).
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).
69. Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274-293 (2012).
70. Csibi, A. et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153, 840-854 (2013).
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).
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).
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).
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).
75. O ATP synthase. Nature Cell Biol. 13, 1224-1233 (2011).
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)
77. Perkins, N. D. The diverse and complex roles of NF-κB subunits in cancer. Nature Rev. Cancer 12, 121-132 (2012).
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).
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).
80. Mauro, C. et al. NF-κB controls energy homeostasis and metabolic adaptation by upregulating mitochondrial respiration. Nature Cell Biol. 13, 1272-1279 (2011).
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).
82. Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107-120 (2006).
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).
84. Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650-1653 (2006).
85. Maiuri, M. C. et al. Autophagy regulation by p53. Curr. Opin. Cell Biol. 22, 181-185 (2010).
86. Jiang, P. et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nature Cell Biol. 13, 310-316 (2011).
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).
88. Vousden, K. H. & Ryan, K. M. p53 and metabolism. Nature Rev. Cancer 9, 691-700 (2009).
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).
90. Maddocks, O. D. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542-546 (2013)
91. Denko, N. C. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nature Rev. Cancer 8, 705-713 (2008).
92. 2 sensing and cancer. Nature Rev. Cancer 8, 865-873 (2008).
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).
94. Zundel, W. et al. Loss of PTEN facilitates HIF-1-mediated gene expression. Genes Dev. 14, 391-396 (2000).
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).
96. Garcia-Cao, I. et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell 149, 49-62 (2012).
97. Ortega-Molina, A. et al. Pten positively regulates brown adipose function, energy expenditure, and longevity. Cell. Metab. 15, 382-394 (2012).
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).
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).
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).
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).
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).
103. Wilson, W. R. & Hay, M. P. Targeting hypoxia in cancer therapy. Nature Rev. Cancer 11, 393-410 (2011).
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).
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).
106. Hitosugi, T. et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth. Sci. Signal. 2, ra73 (2009).
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).
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).
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).
110. Anastasiou, D. et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses. Science 334, 1278-1283 (2011).
111. Zhong, L. et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell 140, 280-293 (2010).
112. Sebastian, C. et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 151, 1185-1199 (2012).
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).
114. Mostoslavsky, R. et al. Genomic instability and aginglike phenotype in the absence of mammalian SIRT6. Cell 124, 315-329 (2006).
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).
116. Altieri, D. C. Survivin, cancer networks and pathway-directed drug discovery. Nature Rev. Cancer 8, 61-70 (2008).
117. Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nature Rev. Mol. Cell Biol. 13, 225-238 (2012).
118. Saunders, L. R. & Verdin, E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 26, 5489-5504 (2007).
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).
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).
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).
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).
123. Carracedo, A. et al. A metabolic prosurvival role for PML in breast cancer. J. Clin. Invest. 122, 3088-3100 (2012).
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).
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).
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).
127. Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109-113 (2009).
128. Gottlieb, E. & Tomlinson, I. P. Mitochondrial tumour suppressors: a genetic and biochemical update. Nature Rev. Cancer 5, 857-866 (2005).
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).
130. Letouze, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739-752 (2013).
131. 2. Free Radic. Biol. Med. 52, 160-166 (2012).
132. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765-773 (2009).
133. Dang, L., Jin, S. & Su, S. M. IDH mutations in glioma and acute myeloid leukemia. Trends Mol. Med. 16, 387-397 (2010).
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).
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).
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).
137. Sreekumar, A. et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910-914 (2009).
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).
139. Zhao, S. et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1α. Science 324, 261-265 (2009).
140. Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17-30 (2011).
141. Koivunen, P. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484-488 (2012).
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).
143. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474-478 (2012).
144. Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479-483 (2012).
145. Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656-659 (2012).
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).
147. Losman, J. A. et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621-1625 (2013).
148. Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380-384 (2012).
149. Mullen, A. R. et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481, 385-388 (2012)
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).
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).
152. Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203 (2011).
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).
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).
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).
156. Goldin, N. et al. Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene 27, 4636-4643 (2008).
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).
158. Klippel, S. et al. Methyljasmonate displays in vitro and in vivo activity against multiple myeloma cells. Br. J. Haematol. 159, 340-351 (2012).
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).
160. Shoshan, M. C. 3-bromopyruvate: targets and outcomes. J. Bioenerg. Biomembr. 44, 7-15 (2012).
161. Hamanaka, R. B. & Chandel, N. S. Targeting glucose metabolism for cancer therapy. J. Exp. Med. 209, 211-215 (2012).
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).
163. Telang, S. et al. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 25, 7225-7234 (2006).
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).
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).
166. Goldberg, M. S. & Sharp, P. A. Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J. Exp. Med. 209, 217-224 (2012).
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).
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).
169. Gautier, E. L. et al. HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myelo-proliferative disorders. J. Exp. Med. 210, 339-353 (2013).
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).
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. 11 2, 849-859 (2011).
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).
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).
174. De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651-663 (2013).
175. Anastasiou, D. et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nature Chem. Biol. 8, 839-847 (2012).
176. Kung, C. et al. Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem. Biol. 19, 1187-1198 (2012).
177. Cortes-Cros, M. et al. M2 isoform of pyruvate kinase is dispensable for tumor maintenance and growth. Proc. Natl Acad. Sci. USA 11 0, 489-494 (2013).
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).
180. Hitosugi, T. et al. Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism. Mol. Cell 44, 864-877 (2011).
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).
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).
183. + channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11, 37-51 (2007).
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).
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).
186. Estrella, V. et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 73, 1524-1535 (2013).
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).
188. Michelakis, E. D. et al. Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34 (2010).
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).
190. Neri, D. & Supuran, C. T. Interfering with pH regulation in tumours as a therapeutic strategy. Nature Rev. Drug Discov. 10, 767-777 (2011).
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).
192. Smyth, J. F. et al. Phase II study of E7070 in patients with metastatic melanoma. Ann. Oncol. 16, 158-161 (2005).
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).
194. Wallace, D. C. Mitochondria and cancer. Nature Rev. Cancer 12, 685-698 (2012).
195. +/NADH balance regulate breast cancer progression. J. Clin. Invest. 123, 1068-1081 (2013).
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).
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).
198. Wise, D. R. & Thompson, C. B. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem. Sci. 35, 427-433 (2010).
199. Fulda, S., Galluzzi, L. & Kroemer, G. Targeting mitochondria for cancer therapy. Nature Rev. Drug Discov. 9, 447-464 (2010).
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).
201. Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642-1646 (2005).
202. Sonveaux, P. et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J. Clin. Invest. 118, 3930-3942 (2008).
203. Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622-626 (2013).
204. Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626-630 (2013)
205. Wang, J. B. et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18, 207-219 (2010).
206. Seltzer, M. J. et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 70, 8981-8987 (2010).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
219. (Min/+) mice. Cancer Lett. 209, 165-169 (2004).
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).
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).
222. Hitosugi, T. et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell 22, 585-600 (2012).
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).
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).
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).
226. Chaneton, B. et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458-462 (2012).
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).
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).
229. Locasale, J. W. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genet. 43, 869-874 (2011).
230. Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346-350 (2011).
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).
232. Bach, S. J. & Swaine, D. The effect of arginase on the retardation of tumour growth. Br. J. Cancer 19, 379-386 (1965).
233. Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040-1044 (2012).
234. Muller, H. J. & Boos, J. Use of l-asparaginase in childhood ALL. Crit. Rev. Oncol. Hematol. 28, 97-113 (1998).
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).
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).
237. Sabatini, D. M. mTOR and cancer: insights into a complex relationship. Nature Rev. Cancer 6, 729-734 (2006).
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).
239. Frezza, C. et al. Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival. PloS ONE 6, e24411 (2011).
240. Menendez, J. A. & Lupu, R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Rev. Cancer 7, 763-777 (2007).
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).
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).
243. Hatzivassiliou, G. et al. AT P citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 8, 311-321 (2005).
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).
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).
246. Yalcin, A. et al. Selective inhibition of choline kinase simultaneously attenuates MAPK and PI3K/AKT signaling. Oncogene 29, 139-149 (2010).
247. Nomura, D. K. et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140, 49-61 (2010).
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).
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).
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).
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).
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).
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).
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).
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).
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).
257. Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109-1112 (2011).
258. Ma, Y., Galluzzi, L., Zitvogel, L. & Kroemer, G. Autophagy and cellular immune responses. Immunity 39, 211-227 (2013).
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).
260. Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823-837 (2009).
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).
262. Li, T. et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269-1283 (2012).
263. Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449-460 (2013).
264. Locasale, J. W. & Cantley, L. C. Metabolic flux and the regulation of mammalian cell growth. Cell. Metab. 14, 443-451 (2011).
265. Galluzzi, L., Kepp, O. & Kroemer, G. Mitochondria: master regulators of danger signalling. Nature Rev. Mol. Cell Biol. 13, 780-788 (2012).
266. Galluzzi, L., Kepp, O., Trojel-Hansen, C. & Kroemer, G. Non-apoptotic functions of apoptosis-regulatory proteins. EMBO Rep. 13, 322-330 (2012).
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).
268. Yang, W. et al. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature 480, 118-122 (2011).
269. Luo, W. et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145, 732-744 (2011).
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).
271. Fritz, V. & Fajas, L. Metabolism and proliferation share common regulatory pathways in cancer cells. Oncogene 29, 4369-4377 (2010).
272. Freed-Pastor, W. A. et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148, 244-258 (2012).
273. Munoz-Pinedo, C., El Mjiyad, N. & Ricci, J. E. Cancer metabolism: current perspectives and future directions. Cell Death Dis. 3, e248 (2012).
274. Michalek, R. D. & Rathmell, J. C. The metabolic life and times of a T-cell. Immunol. Rev. 236, 190-202 (2010).
275. Altman, B. J. & Dang, C. V. Normal and cancer cell metabolism: lymphocytes and lymphoma. FEBS J. 279, 2598-2609 (2012).
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).
277. Pietras, K. & Ostman, A. Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 316, 1324-1331 (2010).
278. Nagaraj, S. & Gabrilovich, D. I. Myeloid-derived suppressor cells in human cancer. Cancer J. 16, 348-353 (2010).
279. Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Med. 17, 1498-1503 (2011).
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).
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).
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).
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).
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).
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).
286. Vander Heiden, M. G. et al. Identification of small molecule inhibitors of pyruvate kinase M2. Biochem. Pharmacol. 79, 1118-1124 (2010).