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Impacts of S-Nitrosylation in Cancer

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Nitric Oxide and Cancer: Pathogenesis and Therapy

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Abstract

From its diminutive size and ephemeral nature to its lipophilicity and ability to rapidly diffuse across cell membranes, nitric oxide (NO) is a highly effective signal molecule. In this capacity, NO regulates the activity of a wide range of target proteins through its central function in S-nitrosylation. In the past decade, S-nitrosylation signaling events have garnered an increasing amount of interest with regard to their impacts on malignant neoplasms. In this chapter, we review both the pathogenic and prospective therapeutic roles of S-nitrosylation in cancer biology.

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Abbreviations

AGT:

O6-alkylguanine-DNA alkyltransferase

EGFR:

Epithelial growth factor receptor

eNOS:

Endothelial Nitric Oxide Synthase

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

HIF-1:

Hypoxia-inducible factor 1

iNOS:

Inducible Nitric Oxide Synthase

NOS:

Nitric Oxide Synthase

nNOS:

Neuronal Nitric Oxide Synthase

SNO:

S-nitrosothiol

References

  1. Osorio J, Recchia F. The role of nitric oxide in metabolism regulation: from basic sciences to the clinical setting. Intensiv Care Med. 2000;26(9):1395–98.

    Article  CAS  Google Scholar 

  2. Moncada S. Nitric oxide: discovery and Impact on clinical medicine. J Royal Soc Med. 1999;92(4):164–9.

    CAS  Google Scholar 

  3. Umansky V, Shirrmacher V. Nitric oxide-induced apoptosis in Tumor Cells. Adv Cancer Res. 2001;82:107–31.

    CAS  PubMed  Google Scholar 

  4. Albina J, Reichner J. Role of nitric oxide in mediation of macrophage cytotoxicity and apoptosis. Cancer Metastasis Rev. 1998;17(1):39–53.

    Article  CAS  PubMed  Google Scholar 

  5. Li H, Hu J, Xin W, Zhao B. Production and interaction of oxygen and nitric oxide free radicals in PMA stimulated macrophages during the respiratory burst. Redox Rep. 2000;5(6):353–8.

    Article  CAS  PubMed  Google Scholar 

  6. Leiro J, Iglesias R, Paramá A, Sanmartin ML, Ubeira FM. Respiratory burst responses of rat macrophages to microsporidian spores. Exp Parasitol. 2001;98(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  7. Reynolds MM, Witzeling SD, Damodaran VB, et al. Applications for nitric oxide in halting proliferation of tumor cells. Biochem Biophys Res Commun. 2013;431(4):647–51.

    Article  CAS  PubMed  Google Scholar 

  8. Gkaliagkousi E, Ferro A. Nitric oxide signalling in the regulation of cardiovascular and platelet function. Front Biosci. 2011;16:1873–97.

    Article  CAS  Google Scholar 

  9. Somers M, Harrison D. Reactive oxygen species and the control of vasomotor tone. Curr Hypertens Rep. 1999;1(1):102–8.

    Article  CAS  PubMed  Google Scholar 

  10. Wink D, Hines H, Cheng R, et al. Nitric oxide and the redox mechanisms in the immune response. J Leukocyte Biol. 2011;89(6):873–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Binder C, Schulz M, Hiddemann W, Oellerich M. Induction of inducible nitric oxide synthase is an essential part of tumor necrosis factor-alpha-induced apoptosis. Lab Investig. 1999;79(12):1703–12.

    CAS  PubMed  Google Scholar 

  12. Farias-Eisner R, Sherman MP, Aeberhard E, Chaudhuri G. Nitric oxide is an important mediator for tumoricidal activity in vivo. Proc Natl Acad Sci. 1994;91(20):9407–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Sarti P, Forte E, Mastronicola D, Giuffrè A, Arese M. Cytochrome c oxidase and nitric oxide in action: molecular mechanisms and pathophysiological implications. Biochimica et Biophysica Acta (BBA)–Bioenerg. 2012;1817(4):610–19.

    Article  CAS  Google Scholar 

  14. Boyd CS, Cadenas E. Nitric oxide and cell signaling pathways in mitochondrial-dependent apoptosis. Biol Chem. 2002;383:411.

    Article  CAS  PubMed  Google Scholar 

  15. Hughes MN. Chemistry of nitric oxide and related species. In: Robert KP, editor. Methods in enzymology. Vol. 436. Academic; 2008. pp. 3–19. (Is available for purchase from Elsevier Academic).

    Google Scholar 

  16. Andrew PJ, Mayer B. Enzymatic function of nitric oxide synthases. Cardiovasc Res. 1999;43(3):521–31.

    Article  CAS  PubMed  Google Scholar 

  17. Foster MW, Hess DT, Stamler JS. Protein S-nitrosylation in health and disease: a current perspective. Trend Mol Med. 15(9):391–404.

    Google Scholar 

  18. Stamler JS, Simon DI, Osborne JA, et al. S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc Natl Acad Sci. 1992;89(1):444–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Jaffrey SR, Erdjument-Bromage H, Ferris CD, Tempst P, Snyder SH. Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat Cell Biol. 2001;3(2):193–7.

    Article  CAS  PubMed  Google Scholar 

  20. Mannick JB. Regulation of apoptosis by protein S-nitrosylation. Amino Acids. 2007;32(4):523–6.

    Article  CAS  PubMed  Google Scholar 

  21. Benhar M, Stamler JS. A central role for S-nitrosylation in apoptosis. Nat Cell Biol. 2005;7(7):645–6.

    Article  CAS  PubMed  Google Scholar 

  22. Melino G, Bernassola F, Knight R, Corasaniti M, Nistico G, Finazzi-Agro A. S-Nitrosylation regulates apoptosis. Nature. 1997;388:432–3.

    Article  CAS  PubMed  Google Scholar 

  23. Martínez-Ruiz A, Lamas S. Two decades of new concepts in nitric oxide signaling: from the discovery of a gas messenger to the mediation of nonenzymatic posttranslational modifications. IUBMB Life. 2009;61(2):91–8.

    Article  PubMed  Google Scholar 

  24. Liu L, Yan Y, Zeng M, et al. Essential roles of S-Nitrosothiols in vascular homeostasis and endotoxic shock. Cell. 2004;116(4):617–28.

    Article  CAS  PubMed  Google Scholar 

  25. Benhar M, Forrester MT, Hess DT, Stamler JS. Regulated protein denitrosylation by cytosolic and mitochondrial thioredoxins. Science. 2008;320(5879):1050–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Trujillo M, Alvarez MaN, Peluffo G, Freeman BA, Radi R. Xanthine oxidase-mediated decomposition of S-Nitrosothiols. Jf Biol Chem. 1998;273(14):7828–34.

    Article  CAS  Google Scholar 

  27. Fukumura D, Kashiwagi S, Jain RK. The role of nitric oxide in tumour progression. Nat Rev Cancer. 2006;6(7):521–34.

    Article  CAS  PubMed  Google Scholar 

  28. Lo H-W, Hsu S-C, Ali-Seyed M, et al. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell. 2005;7(6):575–89.

    Article  CAS  PubMed  Google Scholar 

  29. Ambs S, Merriam WG, Ogunfusika MO, et al. p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nat Med. 1998;4(12):1371–6.

    Article  CAS  PubMed  Google Scholar 

  30. Jenkins DC, Charles IG, Thomsen LL, et al. Roles of nitric oxide in tumor growth. Proc Natl Acad Sci. 1995;92(10):4392–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Cockman ME, Masson N, Mole DR, et al. Hypoxia inducible factor-α binding and ubiquitylation by the von hippel-lindau tumor suppressor protein. J Biol Chem. 2000;275(33):25733–41.

    Article  CAS  PubMed  Google Scholar 

  32. Jaakkola P, Mole DR, Tian Y-M, et al. Targeting of HIF-α to the von hippel-lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292(5516):468–72.

    Article  CAS  PubMed  Google Scholar 

  33. Maxwell PH, Wiesener MS, Chang G-W, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271–5.

    Article  CAS  PubMed  Google Scholar 

  34. Lima B, Lam GKW, Xie L, et al. Endogenous S-nitrosothiols protect against myocardial injury. Proc Natl Acad Sci. 2009;106(15):6297–302.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Palmer LA, Gaston B, Johns RA. Normoxic stabilization of hypoxia-inducible factor-1 expression and activity: redox-dependent effect of nitrogen oxides. Mol Pharmacol. 2000;58(6):1197–203.

    CAS  PubMed  Google Scholar 

  36. Azad N, Vallyathan V, Wang L, et al. S-Nitrosylation of Bcl-2 inhibits its ubiquitin-proteasomal degradation: a novel antiapoptotic mechanism that suppresses apoptosis. J Biol Chem. 2006;281(45):34124–34.

    Article  CAS  PubMed  Google Scholar 

  37. Liu L, Xu-Welliver M, Kanugula S, Pegg AE. Inactivation and degradation of O6-Alkylguanine-DNA alkyltransferase after reaction with nitric oxide. Cancer Res. 2002;62(11):3037–43.

    CAS  PubMed  Google Scholar 

  38. Yu C-X, Li S, Whorton AR. Redox regulation of PTEN by S-Nitrosothiols. Mol Pharmacol. 2005;68(3):847–54.

    CAS  PubMed  Google Scholar 

  39. Calmels S, Hainaut P, Ohshima H. Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein. Cancer Res. 1997;57(16):3365–9.

    CAS  PubMed  Google Scholar 

  40. Pi X, Wu Y, Ferguson JE, Portbury AL, Patterson C. SDF-1α stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration. Proc Natl Acad Sci. 2009;106(14):5675–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Rahman MA, Senga T, Ito S, Hyodo T, Hasegawa H, Hamaguchi M. S-nitrosylation at cysteine 498 of c-Src tyrosine kinase regulates nitric oxide-mediated cell invasion. J Biol Chem. 2010;285(6):3806–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Sharp FR, Bernaudin M. HIF1 and oxygen sensing in the brain. Nat Rev Neurosci. 2004;5(6):437–48.

    Article  CAS  PubMed  Google Scholar 

  43. Martinou J-C, Youle Richard J. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell. 2011;21(1):92–101.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Iyer AKV, Azad N, Wang L, Rojanasakul Y. Role of S-nitrosylation in apoptosis resistance and carcinogenesis. Nitric Oxide. 2008;19(2):146–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011;11(4):289–301.

    Article  CAS  PubMed  Google Scholar 

  46. Schonhoff CM, Daou M-C, Jones SN, Schiffer CA, Ross AH. Nitric oxide-mediated inhibition of Hdm2−p53 binding†. Biochemistry. 2002;41(46):13570–4.

    Article  CAS  PubMed  Google Scholar 

  47. Leon-Bollotte L, Subramaniam S, Cauvard O, et al. S-Nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells. Gastroenterology. 2011;140(7):2009-2018. (e2004).

    Article  PubMed  Google Scholar 

  48. Kornberg MD, Sen N, Hara MR, et al. GAPDH mediates nitrosylation of nuclear proteins. Nat Cell Biol. 2010;12(11):1094–100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Sen N, Hara MR, Kornberg MD, et al. Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol. 2008;10(7):866–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Marshall HE, Hess DT, Stamler JS. S-nitrosylation: physiological regulation of NF-κB. Proc Natl Acad Sci USA. 2004;101(24):8841–2.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Marshall HE, Stamler JS. Nitrosative stress-induced apoptosis through inhibition of NF-κB. J Biol Chem. 2002;277(37):34223–8.

    Article  CAS  PubMed  Google Scholar 

  52. Kelleher ZT, Matsumoto A, Stamler JS, Marshall HE. NOS2 regulation of NF-κB by S-nitrosylation of p65. J Biol Chem. 2007;282(42):30667–72.

    Article  CAS  PubMed  Google Scholar 

  53. Bonavida B, Baritaki S. Dual role of NO donors in the reversal of tumor cell resistance and EMT: downregulation of the NF-κB/Snail/YY1/RKIP circuitry. Nitric Oxide. 2011;24(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  54. Huerta-Yepez S, Vega M, Jazirehi A, et al. Nitric oxide sensitizes prostate carcinoma cell lines to TRAIL-mediated apoptosis via inactivation of NF-[kappa]B and inhibition of Bcl-xL expression. Oncogene. 2004;23(29):4993–5003.

    Article  CAS  PubMed  Google Scholar 

  55. Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the fas ligand, a novel member of the tumor necrosis factor family. Cell. 1993;75(6):1169–78.

    Article  CAS  PubMed  Google Scholar 

  56. Pant V, Lozano G. Limiting the power of p53 through the ubiquitin proteasome pathway. Gene Dev. 2014;28(16):1739–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Hara MR, Agrawal N, Kim SF, et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol. 2005;7(7):665–74.

    Article  CAS  PubMed  Google Scholar 

  58. Guan W, Sha J, Chen X, Xing Y, Yan J, Wang Z. S-Nitrosylation of mitogen activated protein kinase phosphatase-1 suppresses radiation-induced apoptosis. Cancer Lett. 2012;314(2):137–46.

    Article  CAS  PubMed  Google Scholar 

  59. Kang-Decker N, Cao S, Chatterjee S, et al. Nitric oxide promotes endothelial cell survival signaling through S-nitrosylation and activation of dynamin-2. J Cell Sci. 2007;120(3):492–501.

    Article  CAS  PubMed  Google Scholar 

  60. Wang G, Moniri NH, Ozawa K, Stamler JS, Daaka Y. Nitric oxide regulates endocytosis by S-nitrosylation of dynamin. Proc Natl Acad Sci USA. 2006;103(5):1295–300.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Chanvorachote P, Nimmannit U, Lu Y, Talbott S, Jiang B-H, Rojanasakul Y. Nitric oxide regulates lung carcinoma cell anoikis through inhibition of ubiquitin-proteasomal degradation of Caveolin-1. J Biol Chem. 2009;284(41):28476–84.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Nath N, Chattopadhyay M, Pospishil L, et al. JS-K; a nitric oxide-releasing prodrug, modulates β-catenin/TCF signaling in leukemic jurkat cells: evidence of an S-nitrosylated mechanism. Biochem Pharmacol. 2010;80(11):1641–49.

    Article  CAS  PubMed  Google Scholar 

  63. Bonavida B, Baritaki S, Huerta-Yepez S, Vega MI, Chatterjee D, Yeung K. Novel therapeutic applications of nitric oxide donors in cancer: roles in chemo- and immunosensitization to apoptosis and inhibition of metastases. Nitric Oxide. 2008;19(2):152–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

MAB thankfully acknowledges support from the National Science Foundation (1060548), the CVMBS College Council, and the Flint Animal Cancer Center.

Conflicts of Interest

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA

    Tysha N. Medeiros

  2. Department of Animal Sciences, Colorado State University, Fort Collins, CO, USA

    Dana M. Jarigese

  3. Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO, USA

    Melissa A. Edwards & Mark A. Brown

  4. Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA

    Mark A. Brown

  5. Department of Ethnic Studies, Colorado State University, Fort Collins, CO, USA

    Mark A. Brown

  6. Colorado School of Public Health, Fort Collins, CO, USA

    Mark A. Brown

Authors
  1. Tysha N. Medeiros
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  2. Dana M. Jarigese
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  4. Mark A. Brown
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Editor information

Editors and Affiliations

  1. Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California of Los Angeles, Los Angeles, California, USA

    Benjamin Bonavida

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Medeiros, T., Jarigese, D., Edwards, M., Brown, M. (2015). Impacts of S-Nitrosylation in Cancer. In: Bonavida, B. (eds) Nitric Oxide and Cancer: Pathogenesis and Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-13611-0_6

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