Is cancer a disease of abnormal cellular metabolism? New angles on an old idea

Genetics in Medicine

Volumn 10, Issue 11, 2008, Pages 767-777

  DeBerardinis, Ralph J ^a,b  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b NONE   (United States)

Author keywords

Cancer; Glucose; Glutamine; Metabolism; Warburg effect

Indexed keywords

LACTIC ACID;

BLADDER CANCER; BREAST CANCER; CANCER MODEL; CANCER RISK; CARCINOGENESIS; CELL GROWTH; CELL METABOLISM; CELL PROLIFERATION; CHROMOSOME ABERRATION; COLON CANCER; ENDOMETRIUM CANCER; GENE MUTATION; GENETIC MODEL; GLUCOSE INTAKE; HEAD AND NECK CANCER; HUMAN; METABOLIC DISORDER; OVARY CANCER; PHENOTYPE; PROSTATE CANCER; PROTO ONCOGENE; REVIEW; TUMOR GROWTH; TUMOR SUPPRESSOR GENE;

ANIMALS; ENERGY METABOLISM; GENES, TUMOR SUPPRESSOR; GLUCOSE; HUMANS; MUTATION; NEOPLASMS; ONCOGENES; TUMOR CELLS, CULTURED;

EID: 57449087215     PISSN: 10983600     EISSN: None     Source Type: Journal    
DOI: 10.1097/GIM.0b013e31818b0d9b     Document Type: Review

References (102)

1. Warburg O. Uber den stoffwechsel der carcinomzelle. Klin Wochenschr 1925;4:534-536.
2. Warburg O. On respiratory impairment in cancer cells. Science 1956;124:269-270.
3. Krohn KA, Link JM, Mason RP. Molecular imaging of hypoxia. J Nucl Med 2008;49(Suppl 2):129S-148S.
4. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3:721-732.
5. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 2004;4:891-899.
6. Matsumoto S, Hyodo F, Subramanian S, et al. Low-field paramagnetic resonance imaging of tumor oxygenation and glycolytic activity in mice. J Clin Invest 2008;118:1965-1973.
7. Arsham AM, Howell JJ, Simon MC. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem 2003;278:29655-29660.
8. Lum JJ, Bui T, Gruber M, et al. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev 2007;21:1037-1049.
9. Malhotra R, Brosius FC III. Glucose uptake and glycolysis reduce hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes. J Biol Chem 1999;274:12567-12575.
10. Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev 2008;18:54-61.
11. Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E. Energy metabolism in tumor cells. FEBS J 2007;274:1393-1418.
12. Kim JW, Dang CV. Cancer's molecular sweet tooth and the Warburg effect. Cancer Res 2006;668927-8930.
13. Altenberg B, Greulich KO. Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes. Genomics 2004;84:1014-1020.
14. Wang T, Marquardt C, Foker J. Aerobic glycolysis during lymphocyte proliferation. Nature 1976;261:702-705.
15. Brand K. Glutamine and glucose metabolism during thymocyte proliferation. Pathways of glutamine and glutamate metabolism. Biochem J 1985;228:353-361.
16. Newsholme EA, Crabtree B, Ardawi MS. The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells. Biosci Rep 1985;5:393-400.
17. Forbes NS, Meadows AL, Clark DS, Blanch HW. Estradiol stimulates the biosynthetic pathways of breast cancer cells: detection by metabolic flux analysis. Metab Eng 2006;8:639-652.
18. DeBerardinis RJ, Mancuso A, Daikhin E, 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 2007;104:19345-19350.
19. Curi R, Newsholme P, Newsholme EA. Metabolism of pyruvate by isolated rat mesenteric lymphocytes, lymphocyte mitochondria and isolated mouse macrophages. Biochem J 1988;250:383-388.
20. Bauer DE, Harris MH, Plas DR, et al. Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand. FASEB J 2004;18:1303-1305.
21. Warburg O. On the origin of cancer cells. Science 1956;123:309-314.
22. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006;3:177-185.
23. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 2006;3:187-197.
24. Gordan JD, Simon MC. Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev 2007;17:71-77.
25. Ookhtens M, Kannan R, Lyon I, Baker N. Liver and adipose tissue contributions to newly formed fatty acids in an ascites tumor. Am J Physiol 1984;247(1 Pt 2):R146-R153.
26. Kuhajda FP. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 2000;16:202-208.
27. Parlo RA, Coleman PS. Enhanced rate of citrate export from cholesterol-rich hepatoma mitochondria. The truncated Krebs cycle and other metabolic ramifications of mitochondrial membrane cholesterol. J Biol Chem 1984;259:9997-10003.
28. 2 in tumors: further evidence for a persistent truncated Krebs cycle in hepatomas. Biochim Biophys Acta 1986;886:169-176.
29. Eagle H. Nutrition needs of mammalian cells in tissue culture. Science 1955;122:501-514.
30. Kovacevic Z, McGivan JD. Mitochondrial metabolism of glutamine and glutamate and its physiological significance. Physiol Rev 1983;63:547-605.
31. Reitzer LJ, Wice BM, Kennell D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 1979;254:2669-2676.
32. Mates JM, Segura JA, Alonso FJ, Marquez J. Pathways from glutamine to apoptosis. Front Biosci 2006;11:3164-3180.
33. Donadio AC, Lobo C, Tosina M, et al. Antisense glutaminase inhibition modifies the O-GlcNAc pattern and flux through the hexosamine pathway in breast cancer cells. J Cell Biochem 2008;103:800-811.
34. Portais JC, Voisin P, Merle M, Canioni P. Glucose and glutamine metabolism in C6 glioma cells studied by carbon 13 NMR. Biochimie 1996;78:155-164.
35. Yuneva M, Zamboni N, Oefner P, Sachidanandam R, Lazebnik Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 2007;178:93-105.
36. Zhu Z, Jiang W, McGinley JN, Thompson HJ. 2-Deoxyglucose as an energy restriction mimetic agent: effects on mammary carcinogenesis and on mammary tumor cell growth in vitro. Cancer Res 2005;65:7023-7030.
37. Christofk HR, Vander Heiden MG, Harris MH, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 2008;452:230-233.
38. Fantin VR, St-Pierre I, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 2006;9:425-434.
39. Hatzivassiliou G, Zhao F, Bauer DE, et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell 2005:8:311-321.
40. Lobo C, Ruiz-Bellido MA, Aledo JC, Marquez J, Nunez De Castro I, Alonso FJ. Inhibition of glutaminase expression by antisense mRNA decreases growth and tumourigenicity of tumour cells. Biochem J 2000;348 (Pt 2):257-261.
41. Ovejera AA, Houchens DP, Catane R, Sheridan MA, Muggia FM. Efficacy of 6-diazo-5-oxo-L-norleucine and N-[N-gamma-glutamyl-6-diazo-5-oxo-norleucinyl]-6- diazo-5-oxo-norleucine against experimental tumors in conventional and nude mice. Cancer Res 1979; 39:3220-3224.
42. Buzzai M, Bauer DE, Jones RG, et al. The glucose dependence of Akt-transformed cells can be reversed by pharmacologic activation of fatty acid beta-oxidation. Oncogene 2005;24:4165-4173.
43. Buzzai M, Jones RG, Amaravadi RK, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007;67:6745-6752.
44. Ramanathan A, Wang C, Schreiber SL. Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc Natl Acad Sci USA 2005; 102:5992-5997.
45. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.
46. Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB. Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 2001;21:5899-5912.
47. Lum JJ, Bauer DE, Kong M, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 2005;120:237-248.
48. Deberardinis RJ, Lum JJ, Thompson CB. Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth. J Biol Chem 2006;281:37372-37380.
49. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 2008;7:11-20.
50. Kawauchi K, Araki K, Tobiume K, Tanaka N. p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol 2008;10:611-618.
51. Bensaad K, Tsuruta A, Selak MA, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006;126:107-120.
52. Kondoh H, Lleonart ME, Gil J, et al. Glycolytic enzymes can modulate cellular life span. Cancer Res 2005;65:177-185.
53. Matoba S, Kang JG, Patino WD, et al. p53 regulates mitochondrial respiration. Science 2006;312:1650-1653.
54. Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C. PI3K/Akt and apoptosis: size matters. Oncogene 2003;22:8983-8998.
55. Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
56. Chian R, Young S, Danilkovitch-Miagkova A, et al. Phosphatidylinositol 3 kinase contributes to the transformation of hematopoietic ceils by the D816V c-Kit mutant. Blood 2001;98:1365-1373.
57. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707-712.
58. Knobbe CB, Merlo A, Reifenberger G. Pten signaling in gliomas. Neuro Oncol 2002;4:196-211.
59. Pedrero JM, Carracedo DG, Pinto CM, et al. Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int J Cancer 2005;114:242-248.
60. Barata JT, Silva A, Brandao JG, Nadler LM, Cardoso AA, Boussiotis VA. Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med 2004;200:659-669.
61. Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol 2003;23:7315-7328.
62. Elstrom RL, Bauer DE, Buzzai M, et al. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 2004;64:3892-3899.
63. Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB. ATP citrate lyase is an important component of cell growth and transformation. Oncogene 2005;24:6314-6322.
64. Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001;15:807- 826.
65. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 2007;26:3291-3310.
66. Flier JS, Mueckler MM, Usher P, Lodish HF. Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. Science 1987;235:1492-1495.
67. Blum R, Jacob-Hirsch I, Amariglio N, Rechavi G, Kloog Y. Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death. Cancer Res 2005;65:999-1006.
68. Vizan P, Boros LG, Figueras A, et al. K-ras codon-specific mutations produce distinctive metabolic phenotypes in NIH3T3 mice [corrected] fibroblasts. Cancer Res 2005;65:5512-5515.
69. Kole HK, Resnick RJ, Van Doren M, Racker E. Regulation of 6-phosphofructo-1-kinase activity in ras-transformed rat-1 fibroblasts. Arch Biochem Biophp 1991;286:586-590.
70. Telang S, Yalcin A, Clem AL, et al. Ras transformation requires metabolic control by 6-phosphofructo-2-kinase. Oncogene 2006;25:7225-7234.
71. Telang S, Lane AN, Nelson KK, Arumugam S, Chesney J. The oncoprotein H-RasV12 increases mitochondrial metabolism. Mol Cancer 2007;6:77.
72. Nikiforov MA, Chandriani S, O'Connell B, et al. A functional screen for Myc-responsive genes reveals serine hydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism. Mol Cell Biol 2002;22:5793-5800.
73. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001;69:49-54.
74. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000;287:848-851.
75. Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000;26:268-270.
76. Gimenez-Roqueplo AP, Favier J, Rustin P, et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am J Hum Genet 2001;69:1186-1197.
77. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 2002;30:406-410.
78. Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005;7:77-85.
79. Canter JA, Kallianpur AR, Parl FF, Millikan RC. Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women. Cancer Res 2005;65:8028-8033.
80. Liu VW, Wang Y, Yang HJ, et al. Mitochondrial DNA variant 16189T>C is associated with susceptibility to endometrial cancer. Hum Mutat 2003;22:173-174.
81. Petros JA, Baumann AK, Ruiz-Pesini E, et al. mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 2005;102:719-724.
82. Brandon M, Baldi P, Wallace DC. Mitochondrial mutations in cancer. Oncogene 2006;25:4647-4662.
83. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321:1807-1812.
84. Day SE, Kettunen MI, Gallagher FA, et al. Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nat Med 2007;13:1382-1387.
85. Kim BJ, Forbes NS. Flux analysis shows that hypoxia-inducible-factor-1- alpha minimally affects intracellular metabolism in tumor spheroids. Biotechnol Bioeng 2007;96:1167-1182.
86. Cocco P, Todde P, Fomera S, Manca MB, Manca P, Sias AR Mortality in a cohort of men expressing the glucose-6-phosphate dehydrogenase deficiency. Blood 1998;91:706-709.
87. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 2007;47:89-116.
88. Lee HR, Cho JM, Shin DH, et al. Adaptive response to GSH depletion and resistance to L: -buthionine-(S,R)-sulfoximine: involvement of Nrf2 activation. Mol Cell Biochem 2008;318:23-31.
89. Kawachi Y, Xu X, Taguchi S, et al. Attenuation of UVB-induced sunburn reaction and oxidative DNA damage with no alterations in UVB-induced skin carcinogenesis in Nrf2 gene-deficient mice. J Invest Dermatol 2008;128:1773-1779.
90. Cho JM, Manandhar S, Lee HR, Park HM, Kwak MK. Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. Cancer Lett 2008;260:96-108.
91. Iida K, Itoh K, Kumagai Y, et al. Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res 2004;64:6424-6431.
92. Ramos-Gomez M, Kwak MK, Dolan PM, et al. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 2001;98:3410-3415.
93. Jones RG, Plas DR, Kubek S, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005;18:283-293.
94. Mandal S, Guptan P, Owusu-Ansah E, Banerjee U. Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila. Dev Cell 2005;9:843-854.
95. Owusu-Ansah E, Yavari A, Mandal S, Banerjee U. Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nat Genet 2008;40:356-361.
96. Cheung VG, Conlin LK, Weber TM, et al. Natural variation in human gene expression assessed in lymphoblastoid cells. Nat Genet 2003;33:422-425.
97. Langbein S, Zerilli M, Zur Hausen A, et al. Expression of transketolase TKTL1 predicts colon and urothelial cancer patient survival: Warburg effect reinterpreted. Br J Cancer 2006;94:578-585.
98. Krockenberger M, Honig A, Rieger L, et al. Transketolase-like 1 expression correlates with subtypes of ovarian cancer and the presence of distant metastases. Int J Gynecol Cancer 2007;17:101-106.
99. Bosaeus I, Daneryd P, Svanberg E, Lundholm K. Dietary intake and resting energy expenditure in relation to weight loss in unselected cancer patients. Int J Cancer 2001;93:380-383.
100. Tisdale MJ. Molecular pathways leading to cancer cachexia. Physiology (Bethesda) 2005;20:340-348.
101. Chen MK, Espat NJ, Bland KI, Copeland EM, III, Souba WW. Influence of progressive tumor growth on glutamine metabolism in skeletal muscle and kidney. Ann Surg 1993;217:655-666; discussion 666-657.
102. Holroyde CP, Gabuzda TG, Putnam RC, Paul P, Reichard GA. Altered glucose metabolism in metastatic carcinoma. Cancer Res 1975;35:3710-3714.