Cancer Cell Metabolism: A Review
It has been known for decades that cancer cells exhibit enhanced rates of Glucose uptake and glycolysis. Rapidly growing Tumor cells display remarkably different metabolic autonomy from the tissues which they are derived. Tumor cells alter their metabolism to support growth and proliferation. In this study, we have re-examined the metabolism in tumor cells and have made an attempt to bring together the major contributions made to this topic till date. This review in particular highlights the altered metabolism in the high energy demanding tumour cells, genetic changes that alter tumour cell metabolism and the role of metabolic microenvironments that may promote malignant progression.
Keywords: Crabtree, Warburg, Metabolic microenvironments, Hypoxia, pH,
2. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev.Cancer. 2011;11: 8e95. http://dx.doi.org/10.1038/nrc2981.
3. Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012; 491:364e373. http://dx.doi.org/ 10.1038/nature11706.
4. Elstrom RL, Bauer DE, Buzzai M. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004; 64:3892e3899.
5. Tennant, D. A., Duran, R. V., Boulahbel, H. & Gottlieb, E. Metabolic transformation in cancer. Carcinogenesis 30, 1269–1280 (2009).
6. King, A. & Gottlieb, E. Glucose metabolism and programmed cell death: an evolutionary and mechanistic perspective. Curr. Opin. Cell Biol. 21, 885–893 (2009).
7. Tatum, J. L. et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int. J. Radiat. Biol. 82, 699–757 (2006)
8. Hawkins, R. A. & Phelps, M. E. PET in clinical oncology. Cancer Metastasis Rev. 7, 119–142 (1988).
9. Weber, W. A., Avril, N. &Schwaiger, M. Relevance of positron emission tomography (PET) in oncology. Strahlenther. Onkol. 175, 356–373 (1999).
10. Gambhir, S. S. Molecular imaging of cancer with positron emission tomography. Nature Rev. Cancer 2, 683–693 (2002). A well written review on FdG PET imaging.
11. Bos, R. et al. Biologic correlates of 18fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography. J.Clin.Oncol. 20, 379–387 (2002)
12. Mochiki, E. et al. Evaluation of 18F-2-deoxy-2-fluoro-Dglucose positron emission tomography for gastric cancer. World J. Surg. 28, 247–253 (2004).
13. Berg, J. M., Tymoczko, J. L., Stryer L. &Gatto, Jr. G. J. Biochemistry 7th edition (2012).
14. Newsholme, E. A. & Board, M. Application of metabolic control logic to fuel utilization and its significance in tumor cells. Adv. Enzyme Regul. 31, 225–246 (1985)
15. Koppenol, W. H. & Bounds, P. L. The Warburg effect and metabolic efficiency: re-crunching the numbers. Science [online], http://www.sciencemag.org/content/324/5930/1029/reply#sci_el_12397?sid=398be983-ebcd-4502-817d-e3f931b9bc37 (2009)
16. S. Rodríguez Enríquez, O. Juárez, J.S. Rodríguez-Zavala, R. Moreno-Sánchez. Multisite control of the Crabtree effect in ascites hepatoma cells. Eur. J. Biochem. FEBS, 268 (2001), pp. 2512-2519
17. D.H. Koobs Phosphate mediation of the Crabtree and Pasteur effects. Science, 178 (1972), pp. 127-133
18. R. Díaz-Ruiz, N. Avéret, D. Araiza, B. Pinson, S. Uribe Carvajal, A. Devin, M.Rigoulet. Mitochondrial oxidative phosphorylation is regulated by fructose 1, 6-bisphosphate. A possible role in Crabtree effect induction? J. Biol. Chem., 283 (2008), pp. 26948-26955
19. Diaz-Ruiz R, Rigoulet M, Devin A. The Warburg and Crabtree effects: on the origin of cancer cell energy metabolism and of yeast glucose repression. Biochimica Biophys. Acta. 2011;1807:568-576
20. Wojtczak L. The Crabtree effect: a new look at the old problem. Acta Biochim Pol. 1996; 43:361e368.
21. YuV Evtodienko, null, V.V. Teplova, J. Duszyński, K. Bogucka, L. Wojtczak. The role of cytoplasmic [Ca2 +] in glucose-induced inhibition of respiration and oxidative phosphorylation in Ehrlich ascites tumour cells: a novel mechanism of the Crabtree effect. Cell Calcium, 15 (1994), pp. 439-446
22. L. Wojtczak, V.V. Teplova, K. Bogucka, A. Czyż, A. Makowska, M.R. Więckowski, J.Duszyński, Y.V. Evtodienko. Effect of glucose and deoxyglucose on the redistribution of calcium in Ehrlich ascites tumour and Zajdela hepatoma cells and its consequences for mitochondrial energetics. Eur. J. Biochem., 263 (1999), pp. 495-501
23. R. Díaz-Ruiz, S. Uribe-Carvajal, A. Devin, M. Rigoulet, Tumor cell energymetabolism and its common features with yeast metabolism, Biochim. Biophys. Acta 1796 (2009) 252–265.
24. Yang X, Borg LA, Eriksson UJ. Altered metabolism and superoxide generation in neural tissue of rat embryos exposed to high glucose. Am J Physiol. 1997;272: 173e180
V.V. Lemeshko. VDAC electronics: 1. VDAC-hexo(gluco)kinase generator of the mitochondrial outer membrane potential. Biochim. Biophys. Acta, 1838 (2014) pp. 1362-1371
25. Weinhouse S (1976) The Warburg hypothesis ﬁfty years later. Zeitschrift fA_Krebsforschung und Klinische. Onkologie 87(2):115–126
26. S. Rodríguez-Enriquez, A. Marín-Hernández, J.C. Pérez-Gallardo, R. MorenoSánchez,Kinetics of transport and phosphorylation of glucose in cancer cells, J.Cell. Physiol. 221 (2009) 552–559.
27. Warburg, O. Metabolism of tumours. Biochem. Zeitschr. 142, 317–333 (1923).
Nachmansohn, D. German-Jewish Pioneers in Science, 1900–1933 (Springer, New York, 1979).
28. Vander-Heiden MG, Cantley LC, Thompson CB. Understanding the Warburgeffect: the metabolic requirements of cell proliferation. Science. 2009; 324: 1029e1033. http://dx.doi.org/10.1126/science.1160809.
29. Weinhouse S (1976) The Warburg hypothesis ﬁfty years later. Zeitschrift fA_Krebsforschung und Klinische. Onkologie 87(2):115–126
30. 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).
31. Bertout, J. A., Patel, S. A. & Simon, M. C. The impact of O2 availability on human cancer. Nature Rev. Cancer 8, 967–975 (2008).
32. Plas, D. R. & Thompson, C. B. Akt dependent transformation: there is more to growth than just surviving. Oncogene 24, 7435–7442 (2005).
33. Inoki, K., Corradetti, M. N. & Guan, K. L. Dysregulation of the TSC mTOR pathway in human disease. Nature Genet. 37, 19–24 (2005).
34. Kapitsinou, P. P. &Haase, V. H. The VHL tumor suppressor and HIF: insights from genetic studies in mice. Cell Death Differ. 15, 650–659 (2008).
35. Kaelin, W. G. The von Hippel Lindau tumour suppressor protein: O2 sensing and cancer. Nature Rev. Cancer 8, 865–873 (2008).
36. Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF α prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).
37. King, A., Selak, M. A. & Gottlieb, E. Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 25, 4675–4682 (2006).
38. Semenza, G. L. HIF 1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56 (2010).
39. 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)
40. 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).
41. Lu, C. W., Lin, S. C., Chen, K. F., Lai, Y. Y. & Tsai, S. J. Induction of pyruvate dehydrogenase kinase 3by hypoxia inducible factor 1 promotes metabolic switch and drug resistance. J. Biol. Chem. 283, 28106–28114 (2008).
42. Gottlieb, E., Tomlinson, I.P., 2005. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat. Rev. Cancer 5, 857–866.
43. Gordan, J. D. et al. HIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14, 435–446 (2008).
44. Pouyssegur J, Dayan F, Mazure NM. Hypoxia signaling in cancer and approaches to enforce tumour regression. Nature. 2006; 441:437e443.
45. Semenza, G.L., 2007. Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. Biochem. J. 405, 1–9
46. Samuel VT, Choi CS, Phillips TG, Romanelli AJ, Geisler JG, Bhanot S, McKay R, Monia B, Shutter JR, Lindberg RA,et al. 2006. Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Diabetes 55: 2042–2050.
47. Wong, K. K., Engelman, J. A. &Cantley, L. C. Targeting the PI3K signaling pathway in cancer. Curr. Opin. Genet. Dev. 20, 87–90 (2010)
48. Elstrom RL, Bauer DE, Buzzai M. Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004; 64:3892e3899.
49. Fan, Y., Dickman, K. G. &Zong, W. X. Akt and c Myc differentially activate cellular metabolic programs and prime cells to bioenergetic inhibition. J. Biol. Chem. 285, 7324–7333 (2010).
50. Robey, R. B. & Hay, N. Is Akt the “Warburg kinase”? Akt energy metabolism interactions and oncogenesis. Semin. Cancer Biol. 19, 25–31 (2009).
51. Khatri, S., Yepiskoposyan, H., Gallo, C. A., Tandon, P. &Plas, D. R. FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. J. Biol. Chem. 285, 15960–15965 (2010).
52. 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).
53. Arsham, A. M., Plas, D. R., Thompson, C. B. & Simon, M. C. Phosphatidylinositol 3-kinase/Aktsignaling is neither required for hypoxic stabilization of HIF-1a nor sufficient for HIF-1-dependent target gene transcription. J. Biol. Chem. 277, 15162–15170 (2002).
54. Arsham, A. M., Plas, D. R., Thompson, C. B. & Simon, M. C. Akt and hypoxia-inducible factor-1 independently enhance tumor growth and angiogenesis. Cancer Res. 64, 3500–3507 (2004).
55. Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C. &Semenza, G. L. HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol. Cell. Biol. 21, 3995–4004 (2001).
56. Robey, R. B. & Hay, N. Is Akt the “Warburg kinase”? Akt energy metabolism interactions and oncogenesis. Semin. Cancer Biol. 19, 25–31 (2009).
57. Guertin, D. A. & Sabatini, D. M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007)
58. Shackelford, D. B. & Shaw, R. J. The LKB1 AMPK pathway: metabolism and growth control in tumour suppression. Nature Rev. Cancer 9, 563–575 (2009)
59. Yun, J. et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science 325, 1555–1559 (2009).
60. Ramanathan, A., Wang, C. & Schreiber, S. L. Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc. Natl Acad. Sci. USA 102, 5992–5997 (2005).
61. Kikuchi, H., Pino, M. S., Zeng, M., Shirasawa, S. & Chung, D. C. Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1α and -2α in colon cancer. Cancer Res. 69, 8499–8506 (2009).
62. Sears, R., Leone, G., DeGregori, J. & Nevins, J. R. Ras enhances Myc protein stability. Mol. Cell 3, 169–179 (1999)
63. O’Neill Abraham AG (2010) PI3K/Akt-mediated regulation of p53 in cancer. Biochem Soc Trans 42(4):798–803
64. Mathupala, S. P., Heese, C. & Pedersen, P. L. Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J. Biol. Chem. 272, 22776–22780 (1997).
65. Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006)
66. L. Wojtczak, V.V. Teplova, K. Bogucka, A. Czyż, A. Makowska, M.R. Więckowski, J.Duszyński, Y.V. Evtodienko. Effect of glucose and deoxyglucose on the redistribution of calcium in Ehrlich ascites tumour and Zajdela hepatoma cells and its consequences for mitochondrial energetics. Eur. J. Biochem., 263 (1999), pp. 495-501
67. Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006)
68. Stambolic, V. et al. Regulation of PTEN transcription by p53. Mol. Cell 8, 317–325 (2001).
69. Almeida, R. et al. OCT 1 is over expressed in intestinal metaplasia and intestinal gastric carcinomas and binds to, but does not transactivate, CDX2 in gastric cells. J. Pathol. 207, 396–401 (2005).
70. Shakya, A. et al. Oct1 loss of function induces a coordinate metabolic shift that opposes tumorigenicity. Nature Cell Biol. 11, 320–327 (2009)
71. Krogh, A. The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J. Physiol. 52, 409–415 (1919).
72. Griffiths, J. R., McIntyre, D. J., Howe, F. A. & Stubbs, M. Why are cancers acidic? A carrier-mediated diffusion model for H+ transport in the interstitial fluid. Novartis Found. Symp. 240, 46–62 (2001)
73. Helmlinger, G., Yuan, F., Dellian, M. & Jain, R. K. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nature Med. 3, 177–182 (1997)
74. Chresand, T. J., Gillies, R. J. & Dale, B. E. Optimum fiber spacing in a hollow fiber bioreactor. Biotechnol. Bioeng. 32, 983–992 (1988).
75. Secomb, T. W. et al. Theoretical simulation of oxygen transport to tumors by three-dimensional networks of microvessels. Adv. Exp. Med. Biol. 454, 629–634 (1998)
76. Baudelet, C. et al. Physiological noise in murine solid tumors using T2*-weighted gradient echo imaging: a marker for tumor acute hypoxia? Phys. Med. Biol. 49, 3389–3411 (2004).
77. Braun, R. D., Lanzen, J. L. & Dewhirst, M. W. Fourier analysis of fluctuations of oxygen tension and blood flow in R3230Ac tumors and muscle in rats. Am. J. Physiol. 277, H551–H568 (1999)
78. Kimura, H. et al. Fluctuations in red cell flux in tumormicrovessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 56, 5522–5528 (1996).
79. Hill, R. P., De Jaeger, K., Jang, A. & Cairns, R. pH, hypoxia and metastasis. Novartis Found. Symp. 240, 154–165 (2001).
80. Gilead, A. &Neeman, M. Dynamic remodeling of the vascular bed precedes tumor growth: MLS ovariancarcinoma spheroids implanted in nude mice. Neoplasia (New York) 1, 226–230 (1999).
81. Berg, J. M., Tymoczko, J. L., Stryer L. &Gatto, Jr. G. J. Biochemistry 7th edition (2012)
82. Hirota K, Semenza GL. Regulation of hypoxia-inducible factor 1 by prolyl and asparaginyl hydroxylases. BiochemBiophys. Res Commun. 2005; 338:610e616.
83. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ. Targeting of HIFalpha to the von Hippel Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001; 292(5516):468e472.
84. Semenza GL. HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell. 2001;107(1):1e3
85. Harada H, 978-953-307-540-2. In: Prof YongpingYou, ed. Gene Therapy Strategyfor Tumour Hypoxia, Targets in Gene Therapy. InTech; 2011.
86. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basichelix-loop helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U. S. A. 1995;92(12):5510e5514.
87. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 2006; 440(7088):1222e1226.
88. Kim JW, Gao P, Dang CV. Effects of hypoxia on tumour metabolism. Cancer Metastasis Rev. 2007; 26(2):291e298.
89. Rofstad EK. Microenvironment-induced cancer metastasis. Int J Radiat Biol. 2000; 76(5):589e605.
90. Wouters, B. G. &Koritzinsky, M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nature Rev. Cancer 8, 851–864 (2008).
91. Koritzinsky, M. et al. Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J. 25, 1114–1125 (2006).
92. Li, B., Gordon, G. M., Du, C. H., Xu, J. & Du, W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17, 469–480 (2010)
93. Rouschop, K. M. &Wouters, B. G. Regulation of autophagy through multiple independent hypoxic signaling pathways. Curr. Mol. Med. 9, 417–424 (2009)
94. Lagadic-Gossmann, D., Huc, L., and Lecureur, V. (2004). Alterations of intracellular pH homeostasis in apoptosis: origins and roles. Cell Death Differ. 11, 953–961. doi: 10.1038/sj.cdd.4401466
95. Gillies, R. J. (2002). In vivo molecular imaging. J. Cell Biochem. Suppl. 39, 231–238. doi: 10.1002/jcb.10450
96. Gallagher, F. A., Kettunen, M. I., Day, S. E., Hu, D. E., Ardenkjaer-Larsen, J. H., Zandt, R., et al. (2008). Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature 453, 940–943. doi: 10.1038/nature07017
97. Hashim, A.I., Zhang, X., Wojtkowiak, J.W., Martinez, G.V., and Gillis, R.J.(2011). Imaging pH and metastasis. NMR Biomed, 24, 582-91. doi :10.1002/nbm. 1644
98. Raghunand, N., Gatenby, R. A. & Gillies, R. J. Microenvironmental and cellular consequences of altered blood flow in tumors. Br. J. Radiol. 77, S11–S22 (2004).
99. Lee, S. R. et al. Reversible inactivation of the tumor suppressor PTEN by H2O2. J. Biol. Chem. 277, 20336–20342 (2002).
100. Bradley, A. J., Lim, Y. Y., and Singh, F. M. (2011). Imaging features, follow-up, and management of incidentally detected renal lesions. Clin. Radiol. 66, 1129–1139. doi: 10.1016/j.crad.2011.07.044
101. Hanahan, D., and Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646–674. doi: 10.1016/j.cell.2011.02.013
102. Rozhin, J., Sameni, M., Ziegler, G. & Sloane, B. F. Pericellular pH affects distribution and secretion of cathepsin B in malignant cells. Cancer Res. 54, 6517–6525 (1994).
103. Montcourrier, P., Silver, I., Farnoud, R., Bird, I. & Rochefort, H. Breast cancer cells have a high capacity to acidify extracellular milieu by a dual mechanism. Clin. Exp. Metastasis 15, 382–392 (1997).
104. 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).
105. Hussain SP,Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer 2003;3:276–85
106. Harman D (1981) The aging process. Proc Natl Acad Sci U S A 78:7124–7128
107. Storz, P., 2005. Reactive oxygen species in tumor progression. Front Biosci. 10, 1881–1896.
108. Giannoni, E., Buricchi, F., Raugei, G., Ramponi, G. &Chiarugi, P. Intracellular reactive oxygen species activate Src tyrosine kinase during cell adhesion and anchorage dependent cell growth. Mol. Cell. Biol. 25, 6391–6403 (2005).
109. Cao, J. et al. Prdx1 inhibits tumorigenesis via regulating PTEN/AKT activity. EMBO J. 28, 1505–1517 (2009).
110. Gao, P. et al. HIF dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12, 230–238 (2007).
111. Bell, E. L., Emerling, B. M. &Chandel, N. S. Mitochondrial regulation of oxygen sensing. Mitochondrion 5, 322–332 (2005).
112. Ramsey, M. R. & Sharpless, N. E. ROS as a tumour suppressor? Nature Cell Biol. 8, 1213–1215 (2006).
113. Takahashi, A. et al. Mitogenic signalling and the p16INK4a Rb pathway cooperate to enforce irreversible cellular senescence. Nature Cell Biol. 8, 1291–1297 (2006).
114. Garrido, C. et al. Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 13, 1423–1433 (2006).
115. Han, D., Antunes, F., Canali, R., Rettori, D. &Cadenas, E. Voltage dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J. Biol. Chem. 278, 5557–5563 (2003)
116. C.M. Ulrich et al. (eds.), Exercise, Energy Balance, and Cancer, Energy Balance and Cancer 6, 7 DOI 10.1007/978-1-4614-4493-0_2, © Springer Science+Business Media New York 2013
117. M. D. Brand, The sites and topology of mitochondrial superoxide production. Exp. Gerontol. 45, 466–472 (2010).
118. Fenton H.J.H. (1894). Oxidation of tartaric acid in presence of iron. J. Chem. Soc., Trans. 65 (65): 899–911. doi:10.1039/ct8946500899
119. S. G. Rhee, H. A. Woo, I. S. Kil, S. H. Bae, Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides. J. Biol. Chem. 287, 4403–4410 (2012).
120. A. G. Cox, C. C. Winterbourn, M. B. Hampton, Mitochondrial peroxiredoxin involvement in antioxidant defence and redox signalling. Biochem. J. 425, 313–325 (2010).
121. Murphy MP, Mitochondrial thiols in antioxidant protection and redox signaling: Distinct roles for glutathionylation and other thiol modifications. Antioxid. Redox Signal. 16, 476–495 (2012).
122. Collinson EJ, Wheeler GL, Garrido EO, Avery AM, Avery SV, Grant CM. The yeast glutaredoxins are active as glutathione peroxidases. J Biol Chem. 2002 May 10; 277(19):16712-7.
123. Li, B., Gordon, G. M., Du, C. H., Xu, J. & Du, W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17, 469–480 (2010)
124. Ozcan, U. et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29, 541–551 (2008).
125. Nogueira, V. et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14, 458–470 (2008).
126. Chen, W. et al. Direct interaction between Nrf2 and p21Cip1/WAF1 upregulates the Nrf2 mediated antioxidant response. Mol. Cell 34, 663–673 (2009)
127. G. M. DeNicola, F. A. Karreth, T. J. Humpton, A. Gopinathan, C. Wei, K. Frese, D. Mangal, K. H. Yu, C. J. Yeo, E. S. Calhoun, F. Scrimieri, J. M. Winter, R. H. Hruban, C. Iacobuzio-Donahue, S. E. Kern, I. A. Blair, D. A. Tuveson, Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011)
128. G. M. DeNicola, P.-H. Chen, E. Mullarky, J. A. Sudderth, Z. Hu, D. Wu, H. Tang, Y. Xie, J. M. Asara, K. E. Huffman, I. I. Wistuba, J. D. Minna, R. J. DeBerardinis, L. C. Cantley, NRF2 regulates serine biosynthesis in non–small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015)
129. J. Ye, J. Fan, S. Venneti, Y.-W. Wan, B. R. Pawel, J. Zhang, L. W. S. Finley, C. Lu, T. Lindsten, J. R. Cross, G. Qing, Z. Liu, M. C. Simon, J. D. Rabinowitz, C. B. Thompson, Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4, 1406–1417 (2014).
130. I. S. Harris, A. E. Treloar, S. Inoue, M. Sasaki, C. Gorrini, K. C. Lee, K. Y. Yung, D. Brenner, C. B. Knobbe-Thomsen, M. A. Cox, A. Elia, T. Berger, D. W. Cescon, A. Adeoye, A. Brüstle, S. D. Molyneux, J. M. Mason, W. Y. Li, K. Yamamoto, A. Wakeham, H. K. Berman, R. Khokha, S. J. Done, T. J. Kavanagh, C.-W. Lam, T. W. Mak, Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27, 211–222 (2015).
131. D. J. Garama, T. J. Harris, C. L. White, F. J. Rossello, M. Abdul-Hay, D. J. Gough, D. E. Levy, A synthetic lethal interaction between glutathione synthesis and mitochondrial reactive oxygen species provides a tumor-specific vulnerability dependent on STAT3. Mol. Cell. Biol. 35, 3646–3656 (2015).
132. Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W. & Ting, J. P. DJ 1, a cancer and Parkinson’s disease associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc. Natl Acad. Sci. USA 103, 15091–15096 (2006).
133. Gasser, T. et al. Genetic complexity and Parkinson’s disease. Science 277, 388–389 (1997).
134. Kim, R. H. et al. DJ 1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 7, 263–273 (2005)
135. Vaughn, A. E. & Deshmukh, M. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nature Cell Biol. 10, 1477–1483 (2008).
136. Gao, P. et al. c Myc suppression of miR 23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458, 762–765 (2009).
137. Suzuki, S. et al. Phosphate activated glutaminase (GLS2), a p53 inducible regulator of glutamine metabolism and reactive oxygen species. Proc. Natl Acad. Sci. USA 107, 7461–7466 (2010).
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (SeeÂ The Effect of Open Access).