Reactive oxygen species-dependent signaling regulates cancer

Review

Abstract

Historically, it has been assumed that oxidative stress contributes to tumor initiation and progression solely by inducing genomic instability. Recent studies indicate that reactive oxygen species are upregulated in tumors and can lead to aberrant induction of signaling networks that cause tumorigenesis and metastasis. Here we review the role of redox-dependent signaling pathways and transcription factors that regulate tumorigenesis.

Keywords

Mitochondria HIF ROS Metastasis Tumorigenesis NADPH oxidase 

Notes

Acknowledgements

This work was supported by NIH Grant R01CA123067-03 as well as the LUNGevity Foundation and a Consortium of Independent Lung Health Organizations convened by the Respiratory Health Association of Metropolitan Chicago to N.S.C.

References

  1. 1.
    Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P (2008) Redox regulation of cell survival. Antioxid Redox Signal 10:1343–1374PubMedCrossRefGoogle Scholar
  2. 2.
    Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95PubMedGoogle Scholar
  3. 3.
    Thannickal VJ, Fanburg BL (2000) Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279:L1005–L1028PubMedGoogle Scholar
  4. 4.
    Ames BN (1988) Measuring oxidative damage in humans: relation to cancer and ageing. IARC Sci Publ 40:7–16Google Scholar
  5. 5.
    Cerutti PA (1985) Prooxidant states and tumor promotion. Science 227:375–381PubMedCrossRefGoogle Scholar
  6. 6.
    Storz P (2005) Reactive oxygen species in tumor progression. Front Biosci 10:1881–1896PubMedCrossRefGoogle Scholar
  7. 7.
    Imlay JA, Chin SM, Linn S (1988) Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro. Science 240:640–642PubMedCrossRefGoogle Scholar
  8. 8.
    Halliwell B, Gutteridge JM (1992) Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS Lett 307:108–112PubMedCrossRefGoogle Scholar
  9. 9.
    Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD (1999) Cell transformation by the superoxide-generating oxidase Mox1. Nature 401:79–82PubMedCrossRefGoogle Scholar
  10. 10.
    Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189PubMedCrossRefGoogle Scholar
  11. 11.
    Chanock SJ, el Benna J, Smith RM, Babior BM (1994) The respiratory burst oxidase. J Biol Chem 269:24519–24522PubMedGoogle Scholar
  12. 12.
    Babior BM (1999) NADPH oxidase: an update. Blood 93:1464–1476PubMedGoogle Scholar
  13. 13.
    Geiszt M, Kopp JB, Varnai P, Leto TL (2000) Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci USA 97:8010–8014PubMedCrossRefGoogle Scholar
  14. 14.
    Ago T, Kitazono T, Ooboshi H, Iyama T, Han YH, Takada J, Wakisaka M, Ibayashi S, Utsumi H, Iida M (2004) Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase. Circulation 109:227–233PubMedCrossRefGoogle Scholar
  15. 15.
    Arnold RS, Shi J, Murad E, Whalen AM, Sun CQ, Polavarapu R, Parthasarathy S, Petros JA, Lambeth JD (2001) Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1. Proc Natl Acad Sci USA 98:5550–5555PubMedCrossRefGoogle Scholar
  16. 16.
    Arbiser JL, Petros J, Klafter R, Govindajaran B, McLaughlin ER, Brown LF, Cohen C, Moses M, Kilroy S, Arnold RS, Lambeth JD (2002) Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci USA 99:715–720PubMedCrossRefGoogle Scholar
  17. 17.
    Li Q, Harraz MM, Zhou W, Zhang LN, Ding W, Zhang Y, Eggleston T, Yeaman C, Banfi B, Engelhardt JF (2006) Nox2 and Rac1 regulate H2O2-dependent recruitment of TRAF6 to endosomal interleukin-1 receptor complexes. Mol Cell Biol 26:140–154PubMedCrossRefGoogle Scholar
  18. 18.
    Van Buul JD, Fernandez-Borja M, Anthony EC, Hordijk PL (2005) Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Antioxid Redox Signal 7:308–317PubMedCrossRefGoogle Scholar
  19. 19.
    Dong-Yun S, Yu-Ru D, Shan-Lin L, Ya-Dong Z, Lian W (2003) Redox stress regulates cell proliferation and apoptosis of human hepatoma through Akt protein phosphorylation. FEBS Lett 542:60–64PubMedCrossRefGoogle Scholar
  20. 20.
    Turrens JF (2003) Mitochondrial formation of reactive oxygen species. J Physiol 552:335–344PubMedCrossRefGoogle Scholar
  21. 21.
    Boveris A, Cadenas E, Stoppani AO (1976) Role of ubiquinone in the mitochondrial generation of hydrogen peroxide. Biochem J 156:435–444PubMedGoogle Scholar
  22. 22.
    Cadenas E, Boveris A, Ragan CI, Stoppani AO (1977) Production of superoxide radicals and hydrogen peroxide by NADH-ubiquinone reductase and ubiquinol-cytochrome c reductase from beef-heart mitochondria. Arch Biochem Biophys 180:248–257PubMedCrossRefGoogle Scholar
  23. 23.
    Turrens JF, Alexandre A, Lehninger AL (1985) Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys 237:408–414PubMedCrossRefGoogle Scholar
  24. 24.
    Han D, Williams E, Cadenas E (2001) Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space. Biochem J 353:411–416PubMedCrossRefGoogle Scholar
  25. 25.
    Starkov AA, Fiskum G (2001) Myxothiazol induces H2O2 production from mitochondrial respiratory chain. Biochem Biophys Res Commun 281:645–650PubMedCrossRefGoogle Scholar
  26. 26.
    Muller FL, Liu Y, Van Remmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279:49064–49073PubMedCrossRefGoogle Scholar
  27. 27.
    Han D, Antunes F, Canali R, Rettori D, Cadenas E (2003) Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. J Biol Chem 278:5557–5563PubMedCrossRefGoogle Scholar
  28. 28.
    Klimova T, Chandel NS (2008) Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ 15:660–666PubMedCrossRefGoogle Scholar
  29. 29.
    Szatrowski TP, Nathan CF (1991) Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 51:794–798PubMedGoogle Scholar
  30. 30.
    Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ (1997) Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 275:1649–1652PubMedCrossRefGoogle Scholar
  31. 31.
    Maciag A, Sithanandam G, Anderson LM (2004) Mutant K-rasV12 increases COX-2, peroxides and DNA damage in lung cells. Carcinogenesis 25:2231–2237PubMedCrossRefGoogle Scholar
  32. 32.
    Nimnual AS, Taylor LJ, Bar-Sagi D (2003) Redox-dependent downregulation of Rho by Rac. Nat Cell Biol 5:236–241PubMedCrossRefGoogle Scholar
  33. 33.
    Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM, Wahl GM (2002) c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell 9:1031–1044PubMedCrossRefGoogle Scholar
  34. 34.
    Kc S, Carcamo JM, Golde DW (2006) Antioxidants prevent oxidative DNA damage and cellular transformation elicited by the over-expression of c-MYC. Mutat Res 593:64–79Google Scholar
  35. 35.
    Tanaka H, Matsumura I, Ezoe S, Satoh Y, Sakamaki T, Albanese C, Machii T, Pestell RG, Kanakura Y (2002) E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell 9:1017–1029PubMedCrossRefGoogle Scholar
  36. 36.
    Murphy DJ, Junttila MR, Pouyet L, Karnezis A, Shchors K, Bui DA, Brown-Swigart L, Johnson L, Evan GI (2008) Distinct thresholds govern Myc’s biological output in vivo. Cancer Cell 14:447–457PubMedCrossRefGoogle Scholar
  37. 37.
    Shachaf CM, Gentles AJ, Elchuri S, Sahoo D, Soen Y, Sharpe O, Perez OD, Chang M, Mitchel D, Robinson WH, Dill D, Nolan GP, Plevritis SK, Felsher DW (2008) Genomic and proteomic analysis reveals a threshold level of MYC required for tumor maintenance. Cancer Res 68:5132–5142PubMedCrossRefGoogle Scholar
  38. 38.
    Meng TC, Fukada T, Tonks NK (2002) Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell 9:387–399PubMedCrossRefGoogle Scholar
  39. 39.
    Barrett WC, DeGnore JP, Keng YF, Zhang ZY, Yim MB, Chock PB (1999) Roles of superoxide radical anion in signal transduction mediated by reversible regulation of protein-tyrosine phosphatase 1B. J Biol Chem 274:34543–34546PubMedCrossRefGoogle Scholar
  40. 40.
    Zhang HJ, Zhao W, Venkataraman S, Robbins ME, Buettner GR, Kregel KC, Oberley LW (2002) Activation of matrix metalloproteinase-2 by overexpression of manganese superoxide dismutase in human breast cancer MCF-7 cells involves reactive oxygen species. J Biol Chem 277:20919–20926PubMedCrossRefGoogle Scholar
  41. 41.
    Chiarugi P, Fiaschi T, Taddei ML, Talini D, Giannoni E, Raugei G, Ramponi G (2001) Two vicinal cysteines confer a peculiar redox regulation to low molecular weight protein tyrosine phosphatase in response to platelet-derived growth factor receptor stimulation. J Biol Chem 276:33478–33487PubMedCrossRefGoogle Scholar
  42. 42.
    Cumming RC, Lightfoot J, Beard K, Youssoufian H, O’Brien PJ, Buchwald M (2001) Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Nat Med 7:814–820PubMedCrossRefGoogle Scholar
  43. 43.
    Berndt C, Lillig CH, Holmgren A (2007) Thiol-based mechanisms of the thioredoxin and glutaredoxin systems: implications for diseases in the cardiovascular system. Am J Physiol Heart Circ Physiol 292:H1227–H1236PubMedCrossRefGoogle Scholar
  44. 44.
    Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 17:2596–2606PubMedCrossRefGoogle Scholar
  45. 45.
    Knebel A, Rahmsdorf HJ, Ullrich A, Herrlich P (1996) Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J 15:5314–5325PubMedGoogle Scholar
  46. 46.
    Sachsenmaier C, Radler-Pohl A, Zinck R, Nordheim A, Herrlich P, Rahmsdorf HJ (1994) Involvement of growth factor receptors in the mammalian UVC response. Cell 78:963–972PubMedCrossRefGoogle Scholar
  47. 47.
    Esposito F, Chirico G, Montesano Gesualdi N, Posadas I, Ammendola R, Russo T, Cirino G, Cimino F (2003) Protein kinase B activation by reactive oxygen species is independent of tyrosine kinase receptor phosphorylation and requires SRC activity. J Biol Chem 278:20828–20834PubMedCrossRefGoogle Scholar
  48. 48.
    Ushio-Fukai M, Alexander RW, Akers M, Yin Q, Fujio Y, Walsh K, Griendling KK (1999) Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells. J Biol Chem 274:22699–22704PubMedCrossRefGoogle Scholar
  49. 49.
    Pages G, Lenormand P, L’Allemain G, Chambard JC, Meloche S, Pouyssegur J (1993) Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci USA 90:8319–8323PubMedCrossRefGoogle Scholar
  50. 50.
    Cowley S, Paterson H, Kemp P, Marshall CJ (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77:841–852PubMedCrossRefGoogle Scholar
  51. 51.
    Cho SY, Klemke RL (2000) Extracellular-regulated kinase activation and CAS/Crk coupling regulate cell migration and suppress apoptosis during invasion of the extracellular matrix. J Cell Biol 149:223–236PubMedCrossRefGoogle Scholar
  52. 52.
    van den Brink MR, Kapeller R, Pratt JC, Chang JH, Burakoff SJ (1999) The extracellular signal-regulated kinase pathway is required for activation-induced cell death of T cells. J Biol Chem 274:11178–11185PubMedCrossRefGoogle Scholar
  53. 53.
    Meloche S, Pouyssegur J (2007) The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 26:3227–3239PubMedCrossRefGoogle Scholar
  54. 54.
    Filmus J, Robles AI, Shi W, Wong MJ, Colombo LL, Conti CJ (1994) Induction of cyclin D1 overexpression by activated ras. Oncogene 9:3627–3633PubMedGoogle Scholar
  55. 55.
    Liu JJ, Chao JR, Jiang MC, Ng SY, Yen JJ, Yang-Yen HF (1995) Ras transformation results in an elevated level of cyclin D1 and acceleration of G1 progression in NIH 3T3 cells. Mol Cell Biol 15:3654–3663PubMedGoogle Scholar
  56. 56.
    Winston JT, Coats SR, Wang YZ, Pledger WJ (1996) Regulation of the cell cycle machinery by oncogenic ras. Oncogene 12:127–134PubMedGoogle Scholar
  57. 57.
    Albanese C, Johnson J, Watanabe G, Eklund N, Vu D, Arnold A, Pestell RG (1995) Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 270:23589–23597PubMedCrossRefGoogle Scholar
  58. 58.
    Lavoie JN, L’Allemain G, Brunet A, Muller R, Pouyssegur J (1996) Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 271:20608–20616PubMedCrossRefGoogle Scholar
  59. 59.
    Weber JD, Raben DM, Phillips PJ, Baldassare JJ (1997) Sustained activation of extracellular-signal-regulated kinase 1 (ERK1) is required for the continued expression of cyclin D1 in G1 phase. Biochem J 326(Pt 1):61–68PubMedGoogle Scholar
  60. 60.
    Balmanno K, Cook SJ (1999) Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells. Oncogene 18:3085–3097PubMedCrossRefGoogle Scholar
  61. 61.
    Pumiglia KM, Decker SJ (1997) Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA 94:448–452PubMedCrossRefGoogle Scholar
  62. 62.
    Sewing A, Wiseman B, Lloyd AC, Land H (1997) High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol Cell Biol 17:5588–5597PubMedGoogle Scholar
  63. 63.
    Woods D, Parry D, Cherwinski H, Bosch E, Lees E, McMahon M (1997) Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol Cell Biol 17:5598–5611PubMedGoogle Scholar
  64. 64.
    Sarsour EH, Venkataraman S, Kalen AL, Oberley LW, Goswami PC (2008) Manganese superoxide dismutase activity regulates transitions between quiescent and proliferative growth. Aging Cell 7:405–417PubMedCrossRefGoogle Scholar
  65. 65.
    Traore K, Sharma R, Thimmulappa RK, Watson WH, Biswal S, Trush MA (2008) Redox-regulation of Erk1/2-directed phosphatase by reactive oxygen species: role in signaling TPA-induced growth arrest in ML-1 cells. J Cell Physiol 216:276–285PubMedCrossRefGoogle Scholar
  66. 66.
    Meng TC, Buckley DA, Galic S, Tiganis T, Tonks NK (2004) Regulation of insulin signaling through reversible oxidation of the protein–tyrosine phosphatases TC45 and PTP1B. J Biol Chem 279:37716–37725PubMedCrossRefGoogle Scholar
  67. 67.
    Havens CG, Ho A, Yoshioka N, Dowdy SF (2006) Regulation of late G1/S phase transition and APC Cdh1 by reactive oxygen species. Mol Cell Biol 26:4701–4711PubMedCrossRefGoogle Scholar
  68. 68.
    Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657PubMedCrossRefGoogle Scholar
  69. 69.
    Lawlor MA, Mora A, Ashby PR, Williams MR, Murray-Tait V, Malone L, Prescott AR, Lucocq JM, Alessi DR (2002) Essential role of PDK1 in regulating cell size and development in mice. EMBO J 21:3728–3738PubMedCrossRefGoogle Scholar
  70. 70.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307:1098–1101PubMedCrossRefGoogle Scholar
  71. 71.
    Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245PubMedCrossRefGoogle Scholar
  72. 72.
    Kandel ES, Hay N (1999) The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res 253:210–229PubMedCrossRefGoogle Scholar
  73. 73.
    Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB, Gray JW (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99–102PubMedCrossRefGoogle Scholar
  74. 74.
    Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22PubMedCrossRefGoogle Scholar
  75. 75.
    Bae GU, Seo DW, Kwon HK, Lee HY, Hong S, Lee ZW, Ha KS, Lee HW, Han JW (1999) Hydrogen peroxide activates p70(S6k) signaling pathway. J Biol Chem 274:32596–32602PubMedCrossRefGoogle Scholar
  76. 76.
    Nemoto S, Finkel T (2002) Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295:2450–2452PubMedCrossRefGoogle Scholar
  77. 77.
    Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG (2002) Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem 277:20336–20342PubMedCrossRefGoogle Scholar
  78. 78.
    Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP (2003) Redox regulation of PI 3-kinase signalling via inactivation of PTEN. EMBO J 22:5501–5510PubMedCrossRefGoogle Scholar
  79. 79.
    Connor KM, Subbaram S, Regan KJ, Nelson KK, Mazurkiewicz JE, Bartholomew PJ, Aplin AE, Tai YT, Aguirre-Ghiso J, Flores SC, Melendez JA (2005) Mitochondrial H2O2 regulates the angiogenic phenotype via PTEN oxidation. J Biol Chem 280:16916–16924PubMedCrossRefGoogle Scholar
  80. 80.
    Yellaturu CR, Bhanoori M, Neeli I, Rao GN (2002) N-Ethylmaleimide inhibits platelet-derived growth factor BB-stimulated Akt phosphorylation via activation of protein phosphatase 2A. J Biol Chem 277:40148–40155PubMedCrossRefGoogle Scholar
  81. 81.
    Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP (2006) Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441:523–527PubMedCrossRefGoogle Scholar
  82. 82.
    Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic–helix–loop–helix–PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514PubMedCrossRefGoogle Scholar
  83. 83.
    Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–1340PubMedCrossRefGoogle Scholar
  84. 84.
    Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54PubMedCrossRefGoogle Scholar
  85. 85.
    Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275PubMedCrossRefGoogle Scholar
  86. 86.
    Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468PubMedCrossRefGoogle Scholar
  87. 87.
    Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472PubMedCrossRefGoogle Scholar
  88. 88.
    Lando D, Peet DJ, Gorman JJ, Whelan DA, Whitelaw ML, Bruick RK (2002) FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev 16:1466–1471PubMedCrossRefGoogle Scholar
  89. 89.
    Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML (2002) Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295:858–861PubMedCrossRefGoogle Scholar
  90. 90.
    Mahon PC, Hirota K, Semenza GL (2001) FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 15:2675–2686PubMedCrossRefGoogle Scholar
  91. 91.
    Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8:705–713PubMedCrossRefGoogle Scholar
  92. 92.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedCrossRefGoogle Scholar
  93. 93.
    Patel SA, Simon MC (2008) Biology of hypoxia-inducible factor-2alpha in development and disease. Cell Death Differ 15:628–634PubMedCrossRefGoogle Scholar
  94. 94.
    Bell EL, Emerling BM, Chandel NS (2005) Mitochondrial regulation of oxygen sensing. Mitochondrion 5:322–332PubMedCrossRefGoogle Scholar
  95. 95.
    Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 95:11715–11720PubMedCrossRefGoogle Scholar
  96. 96.
    Chandel NS, Schumacker PT (1999) Cells depleted of mitochondrial DNA (rho0) yield insight into physiological mechanisms. FEBS Lett 454:173–176PubMedCrossRefGoogle Scholar
  97. 97.
    Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 275:25130–25138PubMedCrossRefGoogle Scholar
  98. 98.
    Agani FH, Pichiule P, Chavez JC, LaManna JC (2000) The role of mitochondria in the regulation of hypoxia-inducible factor 1 expression during hypoxia. J Biol Chem 275:35863–35867PubMedCrossRefGoogle Scholar
  99. 99.
    Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1:401–408PubMedCrossRefGoogle Scholar
  100. 100.
    Brunelle JK, Bell EL, Quesada NM, Vercauteren K, Tiranti V, Zeviani M, Scarpulla RC, Chandel NS (2005) Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab 1:409–414PubMedCrossRefGoogle Scholar
  101. 101.
    Mansfield KD, Guzy RD, Pan Y, Young RM, Cash TP, Schumacker PT, Simon MC (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab 1:393–399PubMedCrossRefGoogle Scholar
  102. 102.
    Bell EL, Klimova TA, Eisenbart J, Moraes CT, Murphy MP, Budinger GR, Chandel NS (2007) The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. J Cell Biol 177:1029–1036PubMedCrossRefGoogle Scholar
  103. 103.
    Hunte C, Palsdottir H, Trumpower BL (2003) Protonmotive pathways and mechanisms in the cytochrome bc1 complex. FEBS Lett 545:39–46PubMedCrossRefGoogle Scholar
  104. 104.
    Ames BN (1983) Dietary carcinogens and anticarcinogens. Oxygen radicals and degenerative diseases. Science 221:1256–1264PubMedCrossRefGoogle Scholar
  105. 105.
    Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V, Bhujwalla ZM, Felsher DW, Cheng L, Pevsner J, Lee LA, Semenza GL, Dang CV (2007) HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12:230–238PubMedCrossRefGoogle Scholar
  106. 106.
    Church SL, Grant JW, Ridnour LA, Oberley LW, Swanson PE, Meltzer PS, Trent JM (1993) Increased manganese superoxide dismutase expression suppresses the malignant phenotype of human melanoma cells. Proc Natl Acad Sci USA 90:3113–3117PubMedCrossRefGoogle Scholar
  107. 107.
    Li JJ, Oberley LW, St Clair DK, Ridnour LA, Oberley TD (1995) Phenotypic changes induced in human breast cancer cells by overexpression of manganese-containing superoxide dismutase. Oncogene 10:1989–2000PubMedGoogle Scholar
  108. 108.
    Kaewpila S, Venkataraman S, Buettner GR, Oberley LW (2008) Manganese superoxide dismutase modulates hypoxia-inducible factor-1 alpha induction via superoxide. Cancer Res 68:2781–2788PubMedCrossRefGoogle Scholar
  109. 109.
    Ma Q, Cavallin LE, Yan B, Zhu S, Duran EM, Wang H, Hale LP, Dong C, Cesarman E, Mesri EA, Goldschmidt-Clermont PJ (2009) Antitumorigenesis of antioxidants in a transgenic Rac1 model of Kaposi’s sarcoma. Proc Natl Acad Sci USA 106(21):8683–8688PubMedCrossRefGoogle Scholar
  110. 110.
    Lowe SW, Cepero E, Evan G (2004) Intrinsic tumour suppression. Nature 432:307–315PubMedCrossRefGoogle Scholar
  111. 111.
    Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, Unterman T, Hay N (2008) Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14:458–470PubMedCrossRefGoogle Scholar
  112. 112.
    Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730PubMedCrossRefGoogle Scholar
  113. 113.
    Dolado I, Nebreda AR (2008) AKT and oxidative stress team up to kill cancer cells. Cancer Cell 14:427–429PubMedCrossRefGoogle Scholar
  114. 114.
    Yu R, Mandlekar S, Harvey KJ, Ucker DS, Kong AN (1998) Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activity. Cancer Res 58:402–408PubMedGoogle Scholar
  115. 115.
    Trachootham D, Zhou Y, Zhang H, Demizu Y, Chen Z, Pelicano H, Chiao PJ, Achanta G, Arlinghaus RB, Liu J, Huang P (2006) Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate. Cancer Cell 10:241–252PubMedCrossRefGoogle Scholar
  116. 116.
    Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284PubMedCrossRefGoogle Scholar
  117. 117.
    Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9:265–273PubMedCrossRefGoogle Scholar
  118. 118.
    Sternlicht MD, Lochter A, Sympson CJ, Huey B, Rougier JP, Gray JW, Pinkel D, Bissell MJ, Werb Z (1999) The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98:137–146PubMedCrossRefGoogle Scholar
  119. 119.
    Lochter A, Srebrow A, Sympson CJ, Terracio N, Werb Z, Bissell MJ (1997) Misregulation of stromelysin-1 expression in mouse mammary tumor cells accompanies acquisition of stromelysin-1-dependent invasive properties. J Biol Chem 272:5007–5015PubMedCrossRefGoogle Scholar
  120. 120.
    Belkhiri A, Richards C, Whaley M, McQueen SA, Orr FW (1997) Increased expression of activated matrix metalloproteinase-2 by human endothelial cells after sublethal H2O2 exposure. Lab Invest 77:533–539PubMedGoogle Scholar
  121. 121.
    Nelson KK, Melendez JA (2004) Mitochondrial redox control of matrix metalloproteinases. Free Radical Biol Med 37:768–784CrossRefGoogle Scholar
  122. 122.
    Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123–127PubMedCrossRefGoogle Scholar
  123. 123.
    Galluzzo M, Pennacchietti S, Rosano S, Comoglio PM, Michieli P (2009) Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis. J Clin Invest 119:865–875PubMedCrossRefGoogle Scholar
  124. 124.
    Vaupel P, Schlenger K, Knoop C, Hockel M (1991) Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res 51:3316–3322PubMedGoogle Scholar
  125. 125.
    Vaupel P, Hockel M, Mayer A (2007) Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9:1221–1235PubMedCrossRefGoogle Scholar
  126. 126.
    Gort EH, Groot AJ, van der Wall E, van Diest PJ, Vooijs MA (2008) Hypoxic regulation of metastasis via hypoxia-inducible factors. Curr Mol Med 8:60–67PubMedCrossRefGoogle Scholar
  127. 127.
    Cannito S, Novo E, Compagnone A, Valfre di Bonzo L, Busletta C, Zamara E, Paternostro C, Povero D, Bandino A, Bozzo F, Cravanzola C, Bravoco V, Colombatto S, Parola M (2008) Redox mechanisms switch on hypoxia-dependent epithelial–mesenchymal transition in cancer cells. Carcinogenesis 29:2267–2278PubMedCrossRefGoogle Scholar
  128. 128.
    Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308:1181–1184PubMedCrossRefGoogle Scholar
  129. 129.
    Funato Y, Michiue T, Asashima M, Miki H (2006) The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled. Nat Cell Biol 8:501–508PubMedCrossRefGoogle Scholar
  130. 130.
    Polyak K, Li Y, Zhu H, Lengauer C, Willson JK, Markowitz SD, Trush MA, Kinzler KW, Vogelstein B (1998) Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 20:291–293PubMedCrossRefGoogle Scholar
  131. 131.
    Chatterjee A, Mambo E, Sidransky D (2006) Mitochondrial DNA mutations in human cancer. Oncogene 25:4663–4674PubMedCrossRefGoogle Scholar
  132. 132.
    Petros JA, Baumann AK, Ruiz-Pesini E, Amin MB, Sun CQ, Hall J, Lim S, Issa MM, Flanders WD, Hosseini SH, Marshall FF, Wallace DC (2005) mtDNA mutations increase tumorigenicity in prostate cancer. Proc Natl Acad Sci USA 102:719–724PubMedCrossRefGoogle Scholar
  133. 133.
    Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi J (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320:661–664PubMedCrossRefGoogle Scholar
  134. 134.
    Gottlieb E, Tomlinson IP (2005) Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5:857–866PubMedCrossRefGoogle Scholar
  135. 135.
    Yankovskaya V, Horsefield R, Tornroth S, Luna-Chavez C, Miyoshi H, Leger C, Byrne B, Cecchini G, Iwata S (2003) Architecture of succinate dehydrogenase and reactive oxygen species generation. Science 299:700–704PubMedCrossRefGoogle Scholar
  136. 136.
    Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69:49–54PubMedCrossRefGoogle Scholar
  137. 137.
    Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW 3rd, Cornelisse CJ, Devilee P, Devlin B (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287:848–851PubMedCrossRefGoogle Scholar
  138. 138.
    Baysal BE, Willett-Brozick JE, Lawrence EC, Drovdlic CM, Savul SA, McLeod DR, Yee HA, Brackmann DE, Slattery WH 3rd, Myers EN, Ferrell RE, Rubinstein WS (2002) Prevalence of SDHB, SDHC, and SDHD germline mutations in clinic patients with head and neck paragangliomas. J Med Genet 39:178–183PubMedCrossRefGoogle Scholar
  139. 139.
    Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, Pan Y, Simon MC, Thompson CB, Gottlieb E (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85PubMedCrossRefGoogle Scholar
  140. 140.
    Guzy RD, Sharma B, Bell E, Chandel NS, Schumacker PT (2008) Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis. Mol Cell Biol 28:718–731PubMedCrossRefGoogle Scholar
  141. 141.
    Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231–2239PubMedCrossRefGoogle Scholar
  142. 142.
    Sudarshan S, Sourbier C, Kong HS, Block K, Romero VV, Yang Y, Galindo C, Mollapour M, Scroggins B, Goode N, Lee MJ, Gourlay CW, Trepel J, Linehan WM, Neckers L (2009) Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and HIF-1α stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol. doi:10.1128/MCB.00483-09

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© Birkhäuser Verlag, Basel/Switzerland 2009

Authors and Affiliations

  1. 1.Division of Pulmonary and Critical Care Medicine, Department of MedicineNorthwestern University Medical SchoolChicagoUSA
  2. 2.Department of Cell and Molecular BiologyNorthwestern University Medical SchoolChicagoUSA

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