Ukr.Biochem.J. 2013; Volume 85, Issue 6, Nov-Dec, pp. 209-217

doi: http://dx.doi.org/10.15407/ubj85.06.209

Reactive oxygen species in signal transduction

L. B. Drobot1, A. A. Samoylenko1, A. V. Vorotnikov2, P. A. Tyurin-Kuzmin2,
A. V. Bazalii1, T. Kietzmann3, V. A. Tkachuk2, S. V. Komisarenko1

1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: drobot@biochem.kiev.ua
2Lomonosov Moscow State University, Faculty of Basic Medicine, Russia;
3Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland;

Reactive oxygen species (ROS) are products of incomplete reduction of oxygen both nonradicals and radicals that function as mediators of redox signaling and oxidative stress depending on their levels in different­ subcellular compartments. Up to date, a huge body of data are accumulated, which supports a role of ROS as “second messengers” in intracellular signaling cascades that control cell growth, proliferation, apoptosis as well as migration and invasion. The current review summarizes data regarding ROS-dependent regulation of signaling­ networks components including MAPK, PI3K/Akt, PKC, NF-κB, Nrf2, FoxO and HIF-1α, and role of ROS in tumorigenesis.

Keywords: , ,


References:

  1. Martindale JL, Holbrook NJ. Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol. 2002 Jul;192(1):1-15. Review. PubMed, CrossRef
  2. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2011 Jan;21(1):103-15. Review. PubMed, PubMedCentral, CrossRef
  3. Vurusaner B, Poli G, Basaga H. Tumor suppressor genes and ROS: complex networks of interactions. Free Radic Biol Med. 2012 Jan 1;52(1):7-18. Review. PubMed, CrossRef
  4. Paulsen CE, Carroll KS. Orchestrating redox signaling networks through regulatory cysteine switches. ACS Chem Biol. 2010 Jan 15;5(1):47-62. Review. PubMed, PubMedCentral, CrossRef
  5. Comba A, Lin YH, Eynard AR, Valentich MA, Fernandez-Zapico ME, Pasqualini ME. Basic aspects of tumor cell fatty acid-regulated signaling and transcription factors. Cancer Metastasis Rev. 2011 Dec;30(3-4):325-42. Review. PubMed, PubMedCentral, CrossRef
  6. Lauth M. RAS and Hedgehog–partners in crime. Front Biosci (Landmark Ed). 2011 Jun 1;16:2259-70. Review. PubMed, CrossRef
  7. Yao H, Ashihara E, Maekawa T. Targeting the Wnt/β-catenin signaling pathway in human cancers. Expert Opin Ther Targets. 2011 Jul;15(7):873-87. Review. PubMed, CrossRef
  8. Ostman A, Frijhoff J, Sandin A, Böhmer FD. Regulation of protein tyrosine phosphatases by reversible oxidation. J Biochem. 2011 Oct;150(4):345-56. Review. PubMed, CrossRef
  9. Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP, Lanfrancone L, Pelicci PG. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature. 1999 Nov 18;402(6759):309-13. PubMed, CrossRef
  10. Lavrovsky Y, Chatterjee B, Clark RA, Roy AK. Role of redox-regulated transcription factors in inflammation, aging and age-related diseases. Exp Gerontol. 2000 Aug;35(5):521-32. Review.  PubMed, CrossRef
  11. Speciale A, Chirafisi J, Saija A, Cimino F. Nutritional antioxidants and adaptive cell responses: an update. Curr Mol Med. 2011 Dec;11(9):770-89. Review.  PubMed, CrossRef
  12. Diebold I, Flügel D, Becht S, Belaiba RS, Bonello S, Hess J, Kietzmann T, Görlach A. The hypoxia-inducible factor-2alpha is stabilized by oxidative stress involving NOX4. Antioxid Redox Signal. 2010 Aug 15;13(4):425-36.  PubMed, CrossRef
  13. Knebel A, Rahmsdorf HJ, Ullrich A, Herrlich P. Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J. 1996 Oct 1;15(19):5314-25.  PubMed, PubMedCentral
  14. Lander HM, Hajjar DP, Hempstead BL, Mirza UA, Chait BT, Campbell S, Quilliam LA. A molecular redox switch on p21(ras). Structural basis for the nitric oxide-p21(ras) interaction. J Biol Chem. 1997 Feb 14;272(7):4323-6.  PubMed, CrossRef
  15. Chan DW, Liu VW, Tsao GS, Yao KM, Furukawa T, Chan KK, Ngan HY. Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells. Carcinogenesis. 2008 Sep;29(9):1742-50.  PubMed, CrossRef
  16. McCubrey JA, Lahair MM, Franklin RA. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1775-89. Review.  PubMed, CrossRef
  17. Handel ML, Watts CK, deFazio A, Day RO, Sutherland RL. Inhibition of AP-1 binding and transcription by gold and selenium involving conserved cysteine residues in Jun and Fos. Proc Natl Acad Sci USA. 1995 May 9;92(10):4497-501.  PubMed, PubMedCentral, CrossRef
  18. Diamond DA, Parsian A, Hunt CR, Lofgren S, Spitz DR, Goswami PC, Gius D. Redox factor-1 (Ref-1) mediates the activation of AP-1 in HeLa and NIH 3T3 cells in response to heat shock. J Biol Chem. 1999 Jun 11;274(24):16959-64.  PubMed, CrossRef
  19. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998 May 1;17(9):2596-606.  PubMed, PubMedCentral, CrossRef
  20. Katagiri K, Matsuzawa A, Ichijo H. Regulation of apoptosis signal-regulating kinase 1 in redox signaling. Methods Enzymol. 2010;474:277-88.  PubMed, CrossRef
  21. Jin HO, Seo SK, Woo SH, Lee HC, Kim ES, Yoo DH, Lee SJ, An S, Choe TB, Kim JI, Hong SI, Rhee CH, Park IC. A combination of sulindac and arsenic trioxide synergistically induces apoptosis in human lung cancer H1299 cells via c-Jun NH2-terminal kinase-dependent Bcl-xL phosphorylation. Lung Cancer. 2008 Sep;61(3):317-27. PubMed, CrossRef
  22. Wang XT, Pei DS, Xu J, Guan QH, Sun YF, Liu XM, Zhang GY. Opposing effects of Bad phosphorylation at two distinct sites by Akt1 and JNK1/2 on ischemic brain injury. Cell Signal. 2007 Sep;19(9):1844-56. PubMed, CrossRef
  23. Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010 May;44(5):479-96. Review.  PubMed, PubMedCentral, CrossRef
  24. Pham CG, Papa S, Bubici C, Zazzeroni F, Franzoso G. In the Crosshairs: NF-κB Targets the JNK Signaling Cascade. Curr Med Chem Anti Inflamm Anti Allergy Agents. 2005 Dec 1;4(6):569-576.  PubMed, PubMedCentral, CrossRef
  25. Parola M, Robino G, Marra F, Pinzani M, Bellomo G, Leonarduzzi G, Chiarugi P, Camandola S, Poli G, Waeg G, Gentilini P, Dianzani MU. HNE interacts directly with JNK isoforms in human hepatic stellate cells. J Clin Invest. 1998 Dec 1;102(11):1942-50.  PubMed, PubMedCentral, CrossRef
  26. Uchida K, Shiraishi M, Naito Y, Torii Y, Nakamura Y, Osawa T. Activation of stress signaling pathways by the end product of lipid peroxidation. 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem. 1999 Jan 22;274(4):2234-42.  PubMed, CrossRef
  27. Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, Cohen P, Fiers W. The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J. 1996 Apr 15;15(8):1914-23.  PubMed, PubMedCentral
  28. Matsukawa J, Matsuzawa A, Takeda K, Ichijo H. The ASK1-MAP kinase cascades in mammalian stress response. J Biochem. 2004 Sep;136(3):261-5. Review.  PubMed, CrossRef
  29. Templeton DJ, Aye MS, Rady J, Xu F, Cross JV. Purification of reversibly oxidized proteins (PROP) reveals a redox switch controlling p38 MAP kinase activity. PLoS One. 2010 Nov 15;5(11):e15012.  PubMed, PubMedCentral, CrossRef
  30. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004 Apr;30(2):193-204. Review.  PubMed, CrossRef
  31. Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal. 2002 May;14(5):381-95. Review.  PubMed, CrossRef
  32. Mehdi MZ, Azar ZM, Srivastava AK. Role of receptor and nonreceptor protein tyrosine kinases in H2O2-induced PKB and ERK1/2 signaling. Cell Biochem Biophys. 2007;47(1):1-10. Review.  PubMed, CrossRef
  33. Shaw M, Cohen P, Alessi DR. The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem J. 1998 Nov 15;336 ( Pt 1):241-6.  PubMed, PubMedCentral, CrossRef
  34. Wang X, McCullough KD, Franke TF, Holbrook NJ. Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem. 2000 May 12;275(19):14624-31.  PubMed, CrossRef
  35. Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem. 2002 Jun 7;277(23):20336-42. PubMed, CrossRef
  36. Huo YY, Li G, Duan RF, Gou Q, Fu CL, Hu YC, Song BQ, Yang ZH, Wu DC, Zhou PK. PTEN deletion leads to deregulation of antioxidants and increased oxidative damage in mouse embryonic fibroblasts. Free Radic Biol Med. 2008 Apr 15;44(8):1578-91. PubMed, CrossRef
  37. Redig AJ, Platanias LC. Protein kinase C signalling in leukemia. Leuk Lymphoma. 2008 Jul;49(7):1255-62. Review. PubMed, CrossRef
  38. Konishi H, Tanaka M, Takemura Y, Matsuzaki H, Ono Y, Kikkawa U, Nishizuka Y. Activation of protein kinase C by tyrosine phosphorylation in response to H2O2. Proc Natl Acad Sci USA. 1997 Oct 14;94(21):11233-7.  PubMed, PubMedCentral, CrossRef
  39. Kazanietz MG. Targeting protein kinase C and “non-kinase” phorbol ester receptors: emerging concepts and therapeutic implications. Biochim Biophys Acta. 2005 Dec 30;1754(1-2):296-304. PubMed, CrossRef
  40. Ferreiro DU, Komives EA. Molecular mechanisms of system control of NF-kappaB signaling by IkappaBalpha. Biochemistry. 2010 Mar 2;49(8):1560-7. Review. PubMed, PubMedCentral, CrossRef
  41. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2011 Jan;21(1):103-15. Review.  PubMed, PubMedCentral, CrossRef
  42. Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol. 2004;44:239-67. Review.  PubMed, CrossRef
  43. Rayet B, Gélinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999 Nov 22;18(49):6938-47. Review.  PubMed, CrossRef
  44. Kamata H, Manabe T, Oka Si, Kamata K, Hirata H. Hydrogen peroxide activates IkappaB kinases through phosphorylation of serine residues in the activation loops. FEBS Lett. 2002 May 22;519(1-3):231-7.  PubMed, CrossRef
  45. Jamaluddin M, Wang S, Boldogh I, Tian B, Brasier AR. TNF-alpha-induced NF-kappaB/RelA Ser(276) phosphorylation and enhanceosome formation is mediated by an ROS-dependent PKAc pathway. Cell Signal. 2007 Jul;19(7):1419-33. PubMed, CrossRef
  46. Ventura C, Maioli M. Protein kinase C control of gene expression. Crit Rev Eukaryot Gene Expr. 2001;11(1-3):243-67. Review. PubMed, CrossRef
  47. Razin E, Szallasi Z, Kazanietz MG, Blumberg PM, Rivera J. Protein kinases C-beta and C-epsilon link the mast cell high-affinity receptor for IgE to the expression of c-fos and c-jun. Proc Natl Acad Sci USA. 1994 Aug 2;91(16):7722-6.  PubMed, PubMedCentral, CrossRef
  48. Matthews JR, Kaszubska W, Turcatti G, Wells TN, Hay RT. Role of cysteine62 in DNA recognition by the P50 subunit of NF-kappa B. Nucleic Acids Res. 1993 Apr 25;21(8):1727-34.  PubMed, PubMedCentral, CrossRef
  49. Matthews JR, Wakasugi N, Virelizier JL, Yodoi J, Hay RT. Thioredoxin regulates the DNA binding activity of NF-kappa B by reduction of a disulphide bond involving cysteine 62. Nucleic Acids Res. 1992 Aug 11;20(15):3821-30.  PubMed, PubMedCentral, CrossRef
  50. Pineda-Molina E, Klatt P, Vázquez J, Marina A, García de Lacoba M, Pérez-Sala D, Lamas S. Glutathionylation of the p50 subunit of NF-kappaB: a mechanism for redox-induced inhibition of DNA binding. Biochemistry. 2001 Nov 27;40(47):14134-42. PubMed, CrossRef
  51. Kabe Y, Ando K, Hirao S, Yoshida M, Handa H. Redox regulation of NF-kappaB activation: distinct redox regulation between the cytoplasm and the nucleus. Antioxid Redox Signal. 2005 Mar-Apr;7(3-4):395-403. Review. PubMed, CrossRef
  52. Kaestner KH, Knochel W, Martinez DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 2000 Jan 15;14(2):142-6.  PubMed
  53. Dansen TB. Forkhead Box O transcription factors: key players in redox signaling. Antioxid Redox Signal. 2011 Feb 15;14(4):559-61. PubMed, CrossRef
  54. Dansen TB, Smits LM, van Triest MH, de Keizer PL, van Leenen D, Koerkamp MG, Szypowska A, Meppelink A, Brenkman AB, Yodoi J, Holstege FC, Burgering BM. Redox-sensitive cysteines bridge p300/CBP-mediated acetylation and FoxO4 activity. Nat Chem Biol. 2009 Sep;5(9):664-72. PubMed, CrossRef
  55. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011 Feb;16(2):123-40. Review. PubMed, CrossRef
  56. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. 2003 Oct;23(20):7198-209.  PubMed, PubMedCentral, CrossRef
  57. Zhao CR, Gao ZH, Qu XJ. Nrf2-ARE signaling pathway and natural products for cancer chemoprevention. Cancer Epidemiol. 2010 Oct;34(5):523-33. Review. PubMed, CrossRef
  58. Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, Yamamoto M. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol. 2008 Apr;28(8):2758-70. PubMed, PubMedCentral, CrossRef
  59. Keum YS, Jeong WS, Kong AN. Chemoprevention by isothiocyanates and their underlying molecular signaling mechanisms. Mutat Res. 2004 Nov 2;555(1-2):191-202. Review. PubMed, CrossRef
  60. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003 Dec;23(24):9361-74. PubMed, PubMedCentral, CrossRef
  61. Hara S, Hamada J, Kobayashi C, Kondo Y, Imura N. Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: suppression of HIF-mediated gene expression by HIF-3alpha. Biochem Biophys Res Commun. 2001 Oct 5;287(4):808-13.  PubMed, CrossRef
  62. Heikkilä M, Pasanen A, Kivirikko KI, Myllyharju J. Roles of the human hypoxia-inducible factor (HIF)-3α variants in the hypoxia response. Cell Mol Life Sci. 2011 Dec;68(23):3885-901. PubMed, CrossRef
  63. Semenza GL. Regulation of physiological responses to continuous and intermittent hypoxia by hypoxia-inducible factor 1. Exp Physiol. 2006 Sep;91(5):803-6. Epub 2006 Jun 1. Review.  PubMed, CrossRef
  64. 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. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001 Oct 5;107(1):43-54.  PubMed, CrossRef
  65. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001 Nov 9;294(5545):1337-40.  PubMed, CrossRef
  66. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001 Apr 20;292(5516):468-72.  PubMed, CrossRef
  67. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001 Apr 20;292(5516):464-8. PubMed, CrossRef
  68. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML. Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science. 2002 Feb 1;295(5556):858-61.  PubMed, CrossRef
  69. Kallio PJ, Okamoto K, O’Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L. Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J. 1998 Nov 16;17(22):6573-86.  PubMed, PubMedCentral, CrossRef
  70. Wang GL, Jiang BH, Semenza GL. Effect of protein kinase and phosphatase inhibitors on expression of hypoxia-inducible factor 1. Biochem Biophys Res Commun. 1995 Nov 13;216(2):669-75.  PubMed, CrossRef
  71. Chen H, Shi H. A reducing environment stabilizes HIF-2alpha in SH-SY5Y cells under hypoxic conditions. FEBS Lett. 2008 Nov 26;582(28):3899-902.  PubMed, PubMedCentral, CrossRef
  72. Kietzmann T, Görlach A. Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression. Semin Cell Dev Biol. 2005 Aug-Oct;16(4-5):474-86. Review.  PubMed, CrossRef
  73. Carrero P, Okamoto K, Coumailleau P, O’Brien S, Tanaka H, Poellinger L. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha. Mol Cell Biol. 2000 Jan;20(1):402-15.  PubMed, PubMedCentral, CrossRef
  74. Jokilehto T, Jaakkola PM. The role of HIF prolyl hydroxylases in tumour growth. J Cell Mol Med. 2010 Apr;14(4):758-70. Review.  PubMed, PubMedCentral, CrossRef
  75. Dimova EY, Michiels C, Kietzmann T. Kinases as upstream regulators of the HIF system: their emerging potential as anti-cancer drug targets. Curr Pharm Des. 2009;15(33):3867-77. Review.  PubMed, CrossRef
  76. Görlach A, Diebold I, Schini-Kerth VB, Berchner-Pfannschmidt U, Roth U, Brandes RP, Kietzmann T, Busse R. Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells: Role of the p22(phox)-containing NADPH oxidase. Circ Res. 2001 Jul 6;89(1):47-54.  PubMed, CrossRef
  77. Richard DE, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J Biol Chem. 2000 Sep 1;275(35):26765-71.  PubMed
  78. Fukuda R, Kelly B, Semenza GL. Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. Cancer Res. 2003 May 1;63(9):2330-4.  PubMed
  79. Wang FS, Wang CJ, Chen YJ, Chang PR, Huang YT, Sun YC, Huang HC, Yang YJ, Yang KD. Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts. J Biol Chem. 2004 Mar 12;279(11):10331-7.  PubMed, CrossRef
  80. Kietzmann T, Jungermann K, Görlach A. Regulation of the hypoxia-dependent plasminogen activator inhibitor 1 expression by MAP kinases. Thromb Haemost. 2003 Apr;89(4):666-73.  PubMed
  81. Gao N, Jiang BH, Leonard SS, Corum L, Zhang Z, Roberts JR, Antonini J, Zheng JZ, Flynn DC, Castranova V, Shi X. p38 Signaling-mediated hypoxia-inducible factor 1alpha and vascular endothelial growth factor induction by Cr(VI) in DU145 human prostate carcinoma cells. J Biol Chem. 2002 Nov 22;277(47):45041-8. PubMed, CrossRef
  82. Liu C, Shi Y, Han Z, Pan Y, Liu N, Han S, Chen Y, Lan M, Qiao T, Fan D. Suppression of the dual-specificity phosphatase MKP-1 enhances HIF-1 trans-activation and increases expression of EPO. Biochem Biophys Res Commun. 2003 Dec 19;312(3):780-6.  PubMed, CrossRef
  83. Marchetti S, Gimond C, Roux D, Gothié E, Pouysségur J, Pagès G. Inducible expression of a MAP kinase phosphatase-3-GFP chimera specifically blunts fibroblast growth and ras-dependent tumor formation in nude mice. J Cell Physiol. 2004 Jun;199(3):441-50. PubMed, CrossRef
  84. Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des. 2010 Jan;16(1):34-44. Review.  PubMed, CrossRef
  85. Raman M, Chen W, Cobb MH. Differential regulation and properties of MAPKs. Oncogene. 2007 May 14;26(22):3100-12. Review.  PubMed, CrossRef
  86. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012 May;24(5):981-90. Review.  PubMed, PubMedCentral, CrossRef
  87. Gupta SC, Hevia D, Patchva S, Park B, Koh W, Aggarwal BB. Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid Redox Signal. 2012 Jun 1;16(11):1295-322. PubMed, PubMedCentral, CrossRef
  88. Kong Q, Beel JA, Lillehei KO. A threshold concept for cancer therapy. Med Hypotheses. 2000 Jul;55(1):29-35. Review.  PubMed, CrossRef
  89. Ramsey MR, Sharpless NE. ROS as a tumour suppressor? Nat Cell Biol. 2006 Nov;8(11):1213-5.  PubMed, CrossRef
  90. Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K, Nakayama KI, Ide T, Saya H, Hara E. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol. 2006 Nov;8(11):1291-7. PubMed, CrossRef
  91. Luanpitpong S, Talbott SJ, Rojanasakul Y, Nimmannit U, Pongrakhananon V, Wang L, Chanvorachote P. Regulation of lung cancer cell migration and invasion by reactive oxygen species and caveolin-1. J Biol Chem. 2010 Dec 10;285(50):38832-40. Epub 2010 Oct 5.
    PubMed, PubMedCentral, CrossRef
  92. Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. 2004 Apr;7(2):97-110. Review.  PubMed, CrossRef
  93. Raj L, Ide T, Gurkar AU, Foley M, Schenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, Lee SW. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature. 2011 Jul 13;475(7355):231-4. PubMed, PubMedCentral, CrossRef
  94. Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov. 2009 Jul;8(7):579-91. Review.  PubMed, CrossRef
  95. Berneis K, Bollag W, Kofler M, Lüthy H. The enhancement of the after effect of ionizing radiation by a cytotoxic methylhydrazine derivative. 1966. Eur J Cancer. 2004 Sep;40(13):1928-33.  PubMed, CrossRef
  96. Pelicano H, Feng L, Zhou Y, Carew JS, Hileman EO, Plunkett W, Keating MJ, Huang P. Inhibition of mitochondrial respiration: a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem. 2003 Sep 26;278(39):37832-9. PubMed, CrossRef
  97. Azzam EI, de Toledo SM, Little JB. Stress signaling from irradiated to non-irradiated cells. Curr Cancer Drug Targets. 2004 Feb;4(1):53-64. Review.  PubMed, CrossRef
  98. Schafer ZT, Grassian AR, Song L, Jiang Z, Gerhart-Hines Z, Irie HY, Gao S, Puigserver P, Brugge JS. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature. 2009 Sep 3;461(7260):109-13. PubMed, PubMedCentral, CrossRef
  99. Lu J, Chew EH, Holmgren A. Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci USA. 2007 Jul 24;104(30):12288-93. PubMed, PubMedCentral, CrossRef
  100. Agarwala SS, Glaspy J, O’Day SJ, Mitchell M, Gutheil J, Whitman E, Gonzalez R, Hersh E, Feun L, Belt R, Meyskens F, Hellstrand K, Wood D, Kirkwood JM, Gehlsen KR, Naredi P. Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J Clin Oncol. 2002 Jan 1;20(1):125-33. PubMed, CrossRef
  101. Yamagishi S, Abe R, Inagaki Y, Nakamura K, Sugawara H, Inokuma D, Nakamura H, Shimizu T, Takeuchi M, Yoshimura A, Bucala R, Shimizu H, Imaizumi T. Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling. Am J Pathol. 2004 Dec;165(6):1865-74. PubMed, PubMedCentral, CrossRef
  102. Druesne-Pecollo N, Latino-Martel P, Norat T, Barrandon E, Bertrais S, Galan P, Hercberg S. Beta-carotene supplementation and cancer risk: a systematic review and metaanalysis of randomized controlled trials. Int J Cancer. 2010 Jul 1;127(1):172-84. Review. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.