Energy transfer in "parasitic" cancer metabolism: Mitochondria are the powerhouse and Achilles' heel of tumor cells

Cell Cycle

Volumn 10, Issue 24, 2011, Pages 4208-4216

  Martinez Outschoorn, Ubaldo E ^a,b   Pestell, Richard G ^a,b   Howell, Anthony ^c   Tykocinski, Mark L ^a   Nagajyothi, Fnu ^d   Machado, Fabiana S ^e   Tanowitz, Herbert B ^d   Sotgia, Federica ^a,c   Lisanti, Michael P ^a,c  

^a THOMAS JEFFERSON UNIVERSITY   (United States)

^b THOMAS JEFFERSON UNIVERSITY   (United States)

^c UNIVERSITY OF MANCHESTER   (United Kingdom)

^d ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^e FEDERAL UNIVERSITY OF MINAS GERAIS   (Brazil)

Author keywords

Aerobic glycolysis; Autophagy; Beta oxidation; Cancer metabolism; Chemo resistance; Drug discovery; Drug resistance; Lipolysis; Metabolic compartments; Metformin; Mitochondria; Mitophagy; Oncometabolite; Oxidative phosphorylation; Parasite; Warburg effect

Indexed keywords

FATTY ACID; GLUTAMINE; KETONE; LACTIC ACID; METFORMIN; STROMAL CELL DERIVED FACTOR 1;

ADIPOCYTE; CACHEXIA; CANCER CELL; CANCER RESISTANCE; CELL CYCLE; CELL FUNCTION; CELL METABOLISM; FATTY ACID OXIDATION; HUMAN; LIPOLYSIS; METASTASIS; MITOCHONDRIAL ENERGY TRANSFER; MITOCHONDRIAL RESPIRATION; MITOCHONDRION; NONHUMAN; OVARY CANCER; OXIDATIVE PHOSPHORYLATION; REVIEW; TUMOR GROWTH;

EID: 84055190706     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.10.24.18487     Document Type: Review

References (81)

1. Rønnov-Jessen L, Bissell MJ. Breast cancer by proxy: can the microenvironment be both the cause and consequence? Trends Mol Med 2009; 15:5-13; PMID:19091631; http://dx.doi.org/10.1016/j.molmed.2008.11.001.
2. Kenny PA, Lee GY, Bissell MJ. Targeting the tumor microenvironment. Front Biosci 2007; 12:3468-74; PMID:17485314; http://dx.doi.org/10.2741/2327.
3. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889; 133:571-3; http://dx.doi.org/10.1016/S0140-6736(00)49915-0.
4. Hart IR. 'Seed and soil' revisited: mechanisms of site-specific metastasis. Cancer Metastasis Rev 1982; 1:5-16; PMID:6764375; http://dx.doi.org/10.1007/BF00049477.
5. Hart IR, Fidler IJ. Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res 1980; 40:2281-7; PMID:7388794.
6. Hart IR, Talmadge JE, Fidler IJ. Metastatic behavior of a murine reticulum cell sarcoma exhibiting organ-specific growth. Cancer Res 1981; 41:1281-7; PMID:7011533.
7. Harris AL. Antiangiogenesis for cancer therapy. Lancet 1997; 349:13-5; PMID:9164441; http://dx.doi.org/10.1016/S0140-6736(97)90014-3.
8. Horak ER, Leek R, Klenk N, LeJeune S, Smith K, Stuart N, et al. Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer. Lancet 1992; 340:1120-4; PMID:1279332; http://dx.doi.org/10.1016/0140-6736(92) 93150-L.
9. Folkman J, Merler E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133:275-88; PMID:4332371; http://dx.doi.org/10.1084/jem.133.2.275.
10. Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 1972; 175:409-16; PMID:5077799; http://dx.doi.org/10.1097/00000658- 197203000-00014.
11. Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, et al. Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol 2011; 43:1045-51; PMID:21300172; http://dx.doi.org/10.1016/j.biocel.2011.01.023.
12. Martinez-Outschoorn UE, Pavlides S, Sotgia F, Lisanti MP. Mitochondrial biogenesis drives tumor cell proliferation. Am J Pathol 2011; 178:1949-52; PMID:21514412; http://dx.doi.org/10.1016/j.ajpath.2011.03.002.
13. Sotgia F, Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Lisanti MP. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res 2011; 13:213; PMID:21867571; http://dx.doi.org/10.1186/bcr2892.
14. Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, et al. Hyperactivation of Oxidative Mitochondrial Metabolism in Epithelial Cancer Cells In Situ: Visualizing the Therapeutic Effects of Metformin in Tumor Tissue. Cell Cycle 2011; 10: In press; PMID:21558814.
15. Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med 2010; 362:875-85; PMID:20220182; http://dx.doi.org/10.1056/NEJMoa0905680.
16. Jacobs TW, Byrne C, Colditz G, Connolly JL, Schnitt SJ. Radial scars in benign breast-biopsy specimens and the risk of breast cancer. N Engl J Med 1999; 340:430-6; PMID:9971867; http://dx.doi.org/10.1056/NEJM199902113400604.
17. Maeshima AM, Niki T, Maeshima A, Yamada T, Kondo H, Matsuno Y. Modified scar grade: a prognostic indicator in small peripheral lung adenocarcinoma. Cancer 2002; 95:2546-54; PMID:12467069; http://dx.doi.org/10.1002/cncr.11006.
18. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999; 59:5002-11; PMID:10519415.
19. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006; 6:392-401; PMID:16572188; http://dx.doi.org/10.1038/nrc1877.
20. McAllister SS, Weinberg RA. Tumor-host interactions: a far-reaching relationship. J Clin Oncol 2010; 28:4022-8; PMID:20644094; http://dx.doi.org/10. 1200/JCO.2010.28.4257.
21. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121:335-48; PMID:15882617; http://dx.doi.org/10.1016/j.cell.2005.02.034.
22. Narsaria N, Mohanty C, Das BK, Mishra SP, Prasad R. Oxidative Stress in Children with Severe Malaria. J Trop Pediatr 2011; In press; PMID:21602230; http://dx.doi.org/10.1093/tropej/fmr043.
23. Dey S, Guha M, Alam A, Goyal M, Bindu S, Pal C, et al. Malarial infection develops mitochondrial pathology and mitochondrial oxidative stress to promote hepatocyte apoptosis. Free Radic Biol Med 2009; 46:271-81; PMID:19015023; http://dx.doi.org/10.1016/j.freeradbiomed.2008.10.032.
24. Ba X, Gupta S, Davidson M, Garg NJ. Trypanosoma cruzi induces the reactive oxygen species-PARP-1-RelA pathway for upregulation of cytokine expression in cardiomyocytes. J Biol Chem 2010; 285:11596-606; PMID:20145242; http://dx.doi.org/10.1074/jbc.M109.076984.
25. Wen JJ, Gupta S, Guan Z, Dhiman M, Condon D, Lui C, et al. Phenyl-alpha-tert-butyl-nitrone and benzonidazole treatment controlled the mitochondrial oxidative stress and evolution of cardiomyopathy in chronic chagasic Rats. J Am Coll Cardiol 2010; 55:2499-508; PMID:20510218; http://dx.doi.org/10.1016/j.jacc.2010.02.030.
26. Gupta S, Dhiman M, Wen JJ, Garg NJ. ROS signalling of inflammatory cytokines during Trypanosoma cruzi infection. Adv Parasitol 2011; 76:153-70; PMID:21884891; http://dx.doi.org/10.1016/B978-0-12-385895-5.00007-4.
27. Gupta S, Wen JJ, Garg NJ. Oxidative Stress in Chagas Disease. Interdiscip Perspect Infect Dis 2009; 2009:190354; PMID:19547716.
28. Romano PS, Arboit MA, Vazquez CL, Colombo MI. The autophagic pathway is a key component in the lysosomal dependent entry of Trypanosoma cruzi into the host cell. Autophagy 2009; 5:6-18; PMID:19115481; http://dx.doi.org/10.4161/ auto.5.1.7160.
29. Nagajyothi F, Desruisseaux MS, Machado FS, Upadhya R, Zhao D, Schwartz GJ, et al. Response of adipose tissue to early infection with Trypanosoma cruzi. J Infect Dis 2012; In press.
30. Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, et al. Oxidative stress in cancer-associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle 2010; 9:3256-76; PMID:20814239; http://dx.doi.org/10.4161/cc.9.16.12553.
31. Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, et al. Autophagy in cancer-associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle 2010; 9:3515-33; PMID:20855962; http://dx.doi.org/10.4161/cc.9.17.12928.
32. Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, et al. HIF1-alpha functions as a tumor promoter in cancer-associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle 2010; 9:3534-51; PMID:20864819; http://dx.doi.org/10.4161/cc.9.17.12908.
33. Migneco G, Whitaker-Menezes D, Chiavarina B, Castello-Cros R, Pavlides S, Pestell RG, et al. Glycolytic cancer-associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: evidence for stromal-epithelial metabolic coupling. Cell Cycle 2010; 9:2412-22; PMID:20562527; http://dx.doi.org/10.4161/cc.9.12.11989.
34. Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, et al. Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the "reverse Warburg effect": a transcriptional informatics analysis with validation. Cell Cycle 2010; 9:2201-19; PMID:20519932; http://dx.doi.org/10.4161/cc.9.11. 11848.
35. Martinez-Outschoorn UE, Whitaker-Menezes D, Lin Z, Flomenberg N, Howell A, Pestell RG, et al. Cytokine production and inflammation drive autophagy in the tumor microenvironment: role of stromal caveolin-1 as a key regulator. Cell Cycle 2011; 10:1784-93; PMID:21566463; http://dx.doi.org/10.4161/cc.10.11.15674.
36. Korkaya H, Wicha MS. Inflammation and autophagy conspire to promote tumor growth. Cell Cycle 2011; 10:2623-4; PMID:21829104; http://dx.doi.org/10.4161/ cc.10.16.16414.
37. Witkiewicz AK, Kline J, Queenan M, Brody JR, Tsirigos A, Bilal E, et al. Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. Cell Cycle 2011; 10:1794-809; PMID:21521946; http://dx.doi.org/10.4161/cc.10.11.15675.
38. Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, et al. Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 2010; 9:3506-14; PMID:20818174; http://dx.doi.org/10. 4161/cc.9.17.12731.
39. Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, et al. Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics. Cell Cycle 2011; 10:1271-86; PMID:21512313; http://dx.doi.org/10.4161/cc.10.8.15330.
40. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, et al. The reverse Warburg effect: aerobic glycolysis in cancer-associated fibroblasts and the tumor stroma. Cell Cycle 2009; 8:3984-4001; PMID:19923890; http://dx.doi.org/10.4161/cc.8.23.10238.
41. Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, et al. The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle 2010; 9:3485-505; PMID:20861672; http://dx.doi.org/10.4161/cc.9.17.12721.
42. Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T, et al. The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox. Cell Cycle 2010; 9:4297-306; PMID:21051947; http://dx.doi.org/10.4161/ cc.9.21.13817.
43. Pavlides S, Vera I, Gandara R, Sneddon S, Pestell R, Mercier I, et al. Warburg Meets Autophagy: Cancer-associated Fibroblasts Accelerate Tumor Growth and Metastasis Via Oxidative Stress, Mitophagy and Aerobic Glycolysis. Antioxid Redox Signal 2012; In press; PMID:21883043.
44. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324:1029-33; PMID:19460998; http://dx.doi.org/10.1126/science.1160809.
45. Kaelin WG Jr, Thompson CB. Q&A: Cancer: clues from cell metabolism. Nature 2010; 465:562-4; PMID:20520704; http://dx.doi.org/10.1038/465562a.
46. Koppenol WH, Bounds PL, Dang CV. Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011; 11:325-37; PMID:21508971; http://dx.doi.org/10.1038/nrc3038.
47. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11:85-95; PMID:21258394; http://dx.doi.org/10.1038/nrc2981.
48. Semenza GL. A return to cancer metabolism. J Mol Med (Berl) 2011; 89:203-4; PMID:21301793.
49. Rabinowitz JD, White E. Autophagy and metabolism. Science 2010; 330:1344-8; PMID:21127245; http://dx.doi.org/10.1126/science.1193497.
50. Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP. Caveolin-1 and Cancer Metabolism in the Tumor Microenvironment: Markers, Models and Mechanisms. Annual Reviews of Pathology: Mechanisms of Disease 2012; 7; In press.
51. Brooks GA. Cell-cell and intracellular lactate shuttles. J Physiol 2009; 587:5591-600; PMID:19805739; http://dx.doi.org/10.1113/jphysiol.2009.178350.
52. Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA 1994; 91:10625-9; PMID:7938003; http://dx.doi.org/10.1073/pnas.91.22.10625.
53. Hashimoto T, Hussien R, Cho HS, Kaufer D, Brooks GA. Evidence for the mitochondrial lactate oxidation complex in rat neurons: demonstration of an essential component of brain lactate shuttles. PLoS ONE 2008; 3:2915; PMID:18698340; http://dx.doi.org/10.1371/journal.pone.0002915.
54. Heller DT, Cahill DM, Schultz RM. Biochemical studies of mammalian oogenesis: metabolic cooperativity between granulosa cells and growing mouse oocytes. Dev Biol 1981; 84:455-64; PMID:20737884; http://dx.doi.org/10.1016/ 0012-1606(81)90415-2.
55. Johnson MT, Freeman EA, Gardner DK, Hunt PA. Oxidative metabolism of pyruvate is required for meiotic maturation of murine oocytes in vivo. Biol Reprod 2007; 77:2-8; PMID:17314311; http://dx.doi.org/10.1095/biolreprod.106. 059899.
56. Stumvoll M, Perriello G, Meyer C, Gerich J. Role of glutamine in human carbohydrate metabolism in kidney and other tissues. Kidney Int 1999; 55:778-92; PMID:10027916; http://dx.doi.org/10.1046/j.1523-755.1999.055003778.x.
57. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, 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 2011; 10:1772-83; PMID:21558814; http://dx.doi.org/10.4161/cc.10.11.15659.
58. Balliet RM, Capparelli C, Guido C, Pestell TG, Martinez-Outschoorn UE, Lin Z, et al. Mitochondrial Oxidative Stress in Cancer-associated Fibroblasts Drives Lactate Production, Promoting Breast Cancer Tumor Growth: Understanding the Aging & Cancer Connection. Cell Cycle 2011; 10;4065-73.
59. Nieman KM, Kenny HA, Penicka C, Ladanyi A, Buell-Gutbrod R, Zillhardt M, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011; In press; PMID:22037646; http://dx.doi.org/10.1038/ nm.2492.
60. van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjerling P, et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 2003; 88:3005-10; PMID:12843134; http://dx.doi.org/10.1210/jc. 2002-021687.
61. Staiger H, Woll J, Haas C, Machicao F, Schleicher ED, Fritsche A, et al. Selective association of plasma non-esterified fatty acid species with circulating interleukin-8 concentrations in humans. Exp Clin Endocrinol Diabetes 2009; 117:21-7; PMID:19053024; http://dx.doi.org/10.1055/s-0028-1085459.
62. Debigaré R, Marquis K, Cote CH, Tremblay RR, Michaud A, LeBlanc P, et al. Catabolic/anabolic balance and muscle wasting in patients with COPD. Chest 2003; 124:83-9; PMID:12853506; http://dx.doi.org/10.1378/chest.124.1.83.
63. Buck M, Chojkier M. Muscle wasting and dedifferentiation induced by oxidative stress in a murine model of cachexia is prevented by inhibitors of nitric oxide synthesis and antioxidants. EMBO J 1996; 15:1753-65; PMID:8617220.
64. Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, et al. Cachexia: a new definition. Clin Nutr 2008; 27:793-9; PMID:18718696; http://dx.doi.org/10.1016/j.clnu.2008.06.013.
65. Kumar NB, Kazi A, Smith T, Crocker T, Yu D, Reich RR, et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Curr Treat Options Oncol 2010; 11:107-17; PMID:21128029; http://dx.doi.org/10.1007/s11864-010-0127-z.
66. Das SK, Eder S, Schauer S, Diwoky C, Temmel H, Guertl B, et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 2011; 333:233-8; PMID:21680814; http://dx.doi.org/10.1126/science.1198973.
67. Tayek JA. A review of cancer cachexia and abnormal glucose metabolism in humans with cancer. J Am Coll Nutr 1992; 11:445-56; PMID:1506607.
68. Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, et al. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 1989; 84:205-13; PMID:2661589; http://dx.doi.org/10.1172/JCI114142.
69. Nurjhan N, Consoli A, Gerich J. Increased lipolysis and its consequences on gluconeogenesis in non-insulin-dependent diabetes mellitus. J Clin Invest 1992; 89:169-75; PMID:1729269; http://dx.doi.org/10.1172/JCI115558.
70. Riccio A, Del Prato S, Vigili de Kreutzenberg S, Tiengo A. Glucose and lipid metabolism in non-insulin-dependent diabetes. Effect of metformin. Diabete Metab 1991; 17:180-4; PMID:1936473.
71. El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 2000; 275:223-8; PMID:10617608; http://dx.doi.org/10.1074/jbc.275.1.223.
72. Zakikhani M, Dowling RJ, Sonenberg N, Pollak MN. The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. Cancer Prev Res (Phila) 2008; 1:369-75; PMID:19138981; http://dx.doi.org/10.1158/1940-6207.CAPR-08-0081.
73. Phoenix KN, Vumbaca F, Fox MM, Evans R, Claffey KP. Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. Breast Cancer Res Treat 2010; 123:333-44; PMID:20204498; http://dx.doi.org/10.1007/s10549-009-0647-z.
74. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009; 32:1620-5; PMID:19564453; http://dx.doi.org/10.2337/dc08-2175.
75. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009; 27:3297-302; PMID:19487376; http://dx.doi.org/10.1200/JCO.2009.19.6410.
76. Martinez-Outschoorn UE, Lin Z, Ko YH, Goldberg AF, Flomenberg N, Wang C, et al. Understanding the metabolic basis of drug resistance: Therapeutic induction of the Warburg effect kills cancer cells. Cell Cycle 2011; 10:2521-8; PMID:21768775; http://dx.doi.org/10.4161/cc.10.15.16584.
77. Martinez-Outschoorn UE, Lin Z, Ko YH, Flomenberg N, Wang C, Pavlides S, et al. Antiestrogen resistance in breast cancer is induced by the tumor microenvironment and can be overcome by inhibiting mitochondrial function in epithelial cancer cells. Cancer Biol Ther 2011; 12:924-38; PMID:22041887.
78. Bensaad K, Cheung EC, Vousden KH. Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J 2009; 28:3015-26; PMID:19713938; http://dx.doi.org/10.1038/emboj.2009.242.
79. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006; 126:107-20; PMID:16839880; http://dx.doi.org/10.1016/j.cell.2006.05.036.
80. Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, et al. The reverse Warburg effect: glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer-associated fibroblasts. Cell Cycle 2010; 9:1960-71; PMID:20495363; http://dx.doi.org/10. 4161/cc.9.10.11601.
81. Sotgia F, Martinez-Outschoorn UE, Lisanti MP. Mitochondrial oxidative stress drives tumor progression and metastasis: should we use antioxidants as a key component of cancer treatment and prevention? BMC Med 2011; 9:62; PMID:21605374; http://dx.doi.org/10.1186/1741-7015-9-62.