A Role for eNOS in Oncogenic Ras-Driven Cancer

Chapter
Part of the Cancer Drug Discovery and Development book series (CDD&D)

Abstract

Nitric oxide (NO) is a highly diffusible gas that is generated by the family of nitric oxide synthases and is increasingly associated with tumorigenesis. While both pro- and anti-tumorigenic properties have been ascribed to NO signaling, recent evidence suggests that eNOS or endothelial nitric oxide synthase promotes tumor formation through its effects on proliferation, cell survival, and angiogenesis. In this chapter we discuss recent evidence that eNOS promotes tumorigenic growth through the activation of the Ras family of proteins.

Keywords

Nitric oxide eNOS Tumorigenesis Pancreatic cancer Ras 

References

  1. Abu-Soud, H.M., Yoho, L.L., and Stuehr, D.J. (1994). Calmodulin controls neuronal nitric-oxide synthase by a dual mechanism. Activation of intra- and interdomain electron transfer. J. Biol. Chem. 269(51), 32047–32050.Google Scholar
  2. Alderton, W.K., Cooper, C.E., and Knowles, R.G. (2001). Nitric oxide synthases: Structure, function and inhibition. Biochem. J. 357(Pt 3), 593–615.PubMedCrossRefGoogle Scholar
  3. Balmain, A., Ramsden, M. Bowden, G.T., and Smith, J. (1984). Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307(5952), 658–660.PubMedCrossRefGoogle Scholar
  4. Bos, J.L. (1989). Ras oncogenes in human cancer: A review. Cancer Res. 49(17), 4682–4689.PubMedGoogle Scholar
  5. Bredt, D.S. and Snyder, S.H. (1990). Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. USA 87(2), 682–685.PubMedCrossRefGoogle Scholar
  6. Brenman, J.E., Chao, D.S., Gee, S.H., McGee, A.W., Craven, S.E., Santillano, D.R., Wu, Z., Huang, F., Xia, H., Peters, M.F., Froehner, S.C., and Bredt, D.S. (1996). Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell 84(5), 757–767.PubMedCrossRefGoogle Scholar
  7. Broholm, H., Braendstrup, O., and Lauritzen, M. (2001). Nitric oxide synthase expression of oligodendrogliomas. Clin. Neuropathol. 20(6), 233–238.PubMedGoogle Scholar
  8. Broholm, H., Rubin, I., Kruse, A., Braendstrup, O., Schmidt, K., Skriver, E.B.., and Lauritzen, M. (2003). Nitric oxide synthase expression and enzymatic activity in human brain tumors. Clin. Neuropathol. 22(6), 273–281.PubMedGoogle Scholar
  9. Campbell, P.M. and Der, C.J. (2004). Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin. Cancer Biol. 14(2), 105–114.PubMedCrossRefGoogle Scholar
  10. Chen, Z.P., Mitchelhill, K.I., Michell, B.J., Stapleton, D., Rodriguez-Crespo, I., Witters, L.A., Power, D.A., Ortiz de Montellano, P.R., and Kemp, B.E. (1999). AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett. 443(3), 285–289.PubMedCrossRefGoogle Scholar
  11. Clavreul, N., Bachschmid, M.M., Hou, X., Shi, C., Idrizovic, A., Ido, Y., Pimentel, D., and Cohen, R.A. (2006). S-glutathiolation of p21ras by peroxynitrite mediates endothelial insulin resistance caused by oxidized low-density lipoprotein. Arterioscler., Thromb. Vasc. Biol. 26(11), 2454–2461.CrossRefGoogle Scholar
  12. Cobbs, C.S., Brenman, J.E., Aldape, K.D., Bredt, D.S., and Israel, M.A. (1995). Expression of nitric oxide synthase in human central nervous system tumors. Cancer Res. 55(4), 727–730.PubMedGoogle Scholar
  13. Colasanti, M., Cavalieri, E., Persichini, T., Mollace, V., Mariotto, S., Suzuki, H., and Lauro, G.M. (1997). Bacterial lipopolysaccharide plus interferon-gamma elicit a very fast inhibition of a Ca2+-dependent nitric-oxide synthase activity in human astrocytoma cells. J. Biol. Chem. 272(12), 7582–7585.PubMedCrossRefGoogle Scholar
  14. Cooper, C.E., Patel, R.P., Brookes, P.S., and Darley-Usmar, V.M. (2002). Nanotransducers in cellular redox signaling: modification of thiols by reactive oxygen and nitrogen species. Trends Biochem. Sci. 27(10), 489–492.PubMedCrossRefGoogle Scholar
  15. Davis, K.L., Martin, E., Turko, I.V., and Murad, F. (2001). Novel effects of nitric oxide. Annu. Rev. Pharmacol. Toxicol. 41, 203–236.PubMedCrossRefGoogle Scholar
  16. Denninger, J.W. and Marletta, M.A. (1999). Guanylate cyclase and the .NO/cGMP signaling pathway. Biochim. Biophys. Acta 1411(2–3), 334–350.PubMedGoogle Scholar
  17. Dimmeler, S., Fleming, I., Fisslthaler, B., Hermann, C., Busse, R., and Zeiher, A.M. (1999). Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399(6736), 601–605.PubMedCrossRefGoogle Scholar
  18. Dodd, F., Limoges, M., Boudreau, R.T., Rowden, G., Murphy, P.R., and Too, C.K. (2000). L-arginine inhibits apoptosis via a NO-dependent mechanism in Nb2 lymphoma cells. J. Cell Biochem. 77(4), 624–634.PubMedCrossRefGoogle Scholar
  19. Doi, C., Noguchi, Y., Marat, D., Saito, A., Fukuzawa, K., Yoshikawa, T., Tsuburaya, A., and Ito, T. (1999). Expression of nitric oxide synthase in gastric cancer. Cancer Lett. 144(2), 161–167.PubMedCrossRefGoogle Scholar
  20. Duda, D.G., Fukumura, D., and Jain, R.K. (2004). Role of eNOS in neovascularization: NO for endothelial progenitor cells. Trends Mol. Med. 10(4), 143–145.PubMedCrossRefGoogle Scholar
  21. Eng, C. 2003. PTEN: one gene, many syndromes. Hum. Mutat. 22(3), 183–198.PubMedCrossRefGoogle Scholar
  22. Engelman, J.A., Luo, J., and Cantley, L.C. (2006). The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7(8), 606–619.PubMedCrossRefGoogle Scholar
  23. Fukumura, D., Gohongi, T., Kadambi, A., Izumi, Y., Ang, J., Yun, C.O., Buerk, D.G., Huang, P.L., and Jain, R.K. (2001). Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc. Natl. Acad. Sci. U S A 98(5), 2604–2609.PubMedCrossRefGoogle Scholar
  24. Fukumura, D., Kashiwagi, S., and Jain, R.K. (2006). The role of nitric oxide in tumour progression. Nat. Rev. Cancer 6(7), 521–534.PubMedCrossRefGoogle Scholar
  25. Fulton, D., Babbitt, R., Zoellner, S., Fontana, J., Acevedo, L., McCabe, T.J., Iwakiri, Y., and Sessa, W.C. (2004). Targeting of endothelial nitric-oxide synthase to the cytoplasmic face of the Golgi complex or plasma membrane regulates Akt- versus calcium-dependent mechanisms for nitric oxide release. J. Biol. Chem. 279(29): 30349–57.PubMedCrossRefGoogle Scholar
  26. Fulton, D., Fontana, J., Sowa, G., Gratton, J.P., Lin, M., Li, K.X., Michell, B., Kemp, B.E., Rodman, D., and Sessa, W.C. (2002). Localization of endothelial nitric-oxide synthase phosphorylated on serine 1179 and nitric oxide in Golgi and plasma membrane defines the existence of two pools of active enzyme. J. Biol. Chem. 277(6), 4277–4284.PubMedCrossRefGoogle Scholar
  27. Fulton, D., Gratton, J.P., McCabe, T.J., Fontana, J., Fujio, Y., Walsh, K., Franke, T.F., Papapetropoulos, A., and Sessa, W.C. (1999). Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399(6736), 597–601.PubMedCrossRefGoogle Scholar
  28. Gachhui, R., Abu-Soud, H.M., Ghosha, D.K., Presta, A., Blazing, M.A., Mayer, B., George, S.E., and Stuehr, D.J. (1998). Neuronal nitric-oxide synthase interaction with calmodulin-troponin C chimeras. J. Biol. Chem. 273(10), 5451–5454.PubMedCrossRefGoogle Scholar
  29. Gachhui, R., Presta, A., Bentley, D.F., Abu-Soud, H.M., McArthur, R., Brudvig, G., Ghosh, D.K., and Stuehr, D.J. (1996). Characterization of the reductase domain of rat neuronal nitric oxide synthase generated in the methylotrophic yeast Pichia pastoris. Calmodulin response is complete within the reductase domain itself. J. Biol. Chem. 271(34), 20594–20602.PubMedCrossRefGoogle Scholar
  30. Gonzalez, E., Kou, R., Lin, A.J., Golan, D.E., and Michel, T. (2002). Subcellular targeting and agonist-induced site-specific phosphorylation of endothelial nitric-oxide synthase. J. Biol. Chem. 277(42), 39554–39560.PubMedCrossRefGoogle Scholar
  31. Gratton, J.P., Lin, M.I., Yu, J., Weiss, E.D., Jiang, Z.L., Fairchild, T.A., Iwakiri, Y., Groszmann, R., Claffey, K.P., Cheng, Y.C., and Sessa, W.C. (2003). Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice. Cancer Cell 4(1), 31–39.PubMedCrossRefGoogle Scholar
  32. Hahn, W.C., Counter, C.M., Lundberg, A.S., Beijersbergen, R.L., Brooks, M.W., and Weinberg, R.A. (1999). Creation of human tumour cells with defined genetic elements. Nature 400(6743), 464–468.PubMedCrossRefGoogle Scholar
  33. Hamad, N.M., Elconin, J.H., Karnoub, A.E., Bai, W., Rich, J.N., Abraham, R.T., Der, C.J., and Counter, C.M. (2002). Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16(16), 2045–2057.PubMedCrossRefGoogle Scholar
  34. Hennessy, B.T., Smith, D.L., Ram, P.T., Lu, Y., and Mills, G.B. (2005). Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov. 4(12), 988–1004.PubMedCrossRefGoogle Scholar
  35. Hess, D.T., Matsumoto, A., Kim, S.O., Marshall, H.E., and Stamler, J.S. (2005). Protein S-nitrosylation: purview and parameters. Nat. Rev. Mol. Cell Biol. 6(2), 150–166.PubMedCrossRefGoogle Scholar
  36. Ikeda, T., Yoshinaga, K., Suzuki, A., Sakurada, A., Ohmori, H., and Horii, A. (2000). Anticorresponding mutations of the KRAS and PTEN genes in human endometrial cancer. Oncol. Rep. 7(3), 567–570.PubMedGoogle Scholar
  37. Iversen, O.H. 1991. The skin tumorigenic and carcinogenic effects of different doses, numbers of dose fractions and concentrations of 7,12-dimethylbenz[a]anthracene in acetone applied on hairless mouse epidermis. Possible implications for human carcinogenesis. Carcinogenesis 12(3), 493–502.PubMedCrossRefGoogle Scholar
  38. Iwata, S., Nakagawa, K., Harada, H., Oka, Y., Kumon, Y., and Sakaki, S. (1999). Endothelial nitric oxide synthase expression in tumor vasculature is correlated with malignancy in human supratentorial astrocytic tumors. Neurosurg. 45(1), 24–28; discussion 29.CrossRefGoogle Scholar
  39. Jaffrey, S.R. and Snyder, S.H. (2001). The biotin switch method for the detection of S-nitrosylated proteins. Sci. STKE 2001(86), PL1.CrossRefGoogle Scholar
  40. Ji, Y., Akerboom, T.P., Sies, H., and Thomas, J.A. (1999). S-nitrosylation and S-glutathiolation of protein sulfhydryls by S-nitroso glutathione. Arch. Biochem. Biophys. 362(1), 67–78.PubMedCrossRefGoogle Scholar
  41. Jones, M.K., Tsugawa, K., Tarnawski, A.S., and Baatar, D. (2004). Dual actions of nitric oxide on angiogenesis: possible roles of PKC, ERK, and AP-1. Biochem. Biophys. Res. Commun. 318(2), 520–528.PubMedCrossRefGoogle Scholar
  42. Karakas, B., Bachman, K.E., and Park, B.H., (2006). Mutation of the PIK3CA oncogene in human cancers. Br. J. Cancer 94(4), 455–459.PubMedCrossRefGoogle Scholar
  43. Kashiwagi, S., Izumi, Y., Gohongi, T., Demou, Z.N., Xu, L., Huang, P.L., Buerk, D.G., Munn, L.L., Jain, R.K., and Fukumura, D. (2005). NO mediates mural cell recruitment and vessel morphogenesis in murine melanomas and tissue-engineered blood vessels. J. Clin. Invest. 115(7), 1816–1827.PubMedCrossRefGoogle Scholar
  44. Kawasaki, K., Smith, Jr., R.S., Hsieh, C.M., Sun, J., Chao, J., and Liao, J.K. (2003). Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates nitric oxide-induced endothelial cell migration and angiogenesis. Mol. Cell Biol. 23(16), 5726–5737.PubMedCrossRefGoogle Scholar
  45. Kemp, C.J., Burns, P.A., Brown, K., Nagase, H., and Balmain, A. (1994). Transgenic approaches to the analysis of ras and p53 function in multistage carcinogenesis. Cold Spring Harb. Symp. Quant. Biol. 59, 427–434.PubMedCrossRefGoogle Scholar
  46. Kiss, H., Schneeberger, C., Tschugguel, W., Lass, H., Huber, J.C., Husslein, P., and Knofler, M. (1998). Expression of endothelial (type III) nitric oxide synthase in cytotrophoblastic cell lines: regulation by hypoxia and inflammatory cytokines. Placenta 19(8), 603–611.PubMedCrossRefGoogle Scholar
  47. Klotz, T., Bloch, W., Jacobs, G., Niggemann, S., Engelmann, U., and Addicks, K. (1999). Immunolocalization of inducible and constitutive nitric oxide synthases in human bladder cancer. Urology 54(3), 416–419.PubMedCrossRefGoogle Scholar
  48. Knowles, R.G. and Moncada, S. (1994). Nitric oxide synthases in mammals. Biochem. J. 298( Pt 2), 249–258.PubMedGoogle Scholar
  49. Kruse, A., Broholm, H., Rubin, I., Schmidt, K., and Lauritzen, M., (2002). Nitric oxide synthase activity in human pituitary adenomas. Acta Neurol. Scand. 106(6), 361–366.PubMedCrossRefGoogle Scholar
  50. Lander, H.M., Hajjar, D.P., Hempstead, B.L., Mirza, U.A., Chait, B.T., Campbell, S., and Quilliam, L.A. (1997). A molecular redox switch on p21(ras). Structural basis for the nitric oxide-p21(ras) interaction. J. Biol. Chem. 272(7), 4323–4326.PubMedCrossRefGoogle Scholar
  51. Lander, H.M., Milbank, A.J., Tauras, J.M., Hajjar, D.P., Hempstead, B.L., Schwartz, G.D., Kraemer, R.T., Mirza, U.A., Chait, B.T., Burk, S.C., and Quilliam, L.A. (1996). Redox regulation of cell signalling. Nature 381(6581), 380–381.PubMedCrossRefGoogle Scholar
  52. Lechner, M., Lirk, P., and Rieder, J. (2005). Inducible nitric oxide synthase (iNOS) in tumor biology: the two sides of the same coin. Semin. Cancer Biol. 15(4), 277–289.PubMedCrossRefGoogle Scholar
  53. Lim, K.H., Ancrile, B.B., Kashatus, D.F., and Counter, C.M. (2008). Tumour maintenance is mediated by eNOS. Nature 452(7187), 646–649.PubMedCrossRefGoogle Scholar
  54. Lin, Z., Chen, S., Ye, C., and Zhu, S. (2003). Nitric oxide synthase expression in human bladder cancer and its relation to angiogenesis. Urol. Res. 31(4), 232–235.PubMedCrossRefGoogle Scholar
  55. Liu, J., Garcia-Cardena, G., and Sessa, W.C. (1995). Biosynthesis and palmitoylation of endothelial nitric oxide synthase: mutagenesis of palmitoylation sites, cysteines-15 and/or -26, argues against depalmitoylation-induced translocation of the enzyme. Biochemistry 34(38), 12333–12340.PubMedCrossRefGoogle Scholar
  56. Liu, J., Hughes, T.E., and Sessa, W.C. (1997). The first 35 amino acids and fatty acylation sites determine the molecular targeting of endothelial nitric oxide synthase into the Golgi region of cells: a green fluorescent protein study. J. Cell Biol. 137(7), 1525–1535.PubMedCrossRefGoogle Scholar
  57. Loibl, S., von Minckwitz, G., Weber, S., Sinn, H.P., Schini-Kerth, V.B., Lobysheva, I., Nepveu, F., Wolf, G., Strebhardt, K., and Kaufmann, M. (2002). Expression of endothelial and inducible nitric oxide synthase in benign and malignant lesions of the breast and measurement of nitric oxide using electron paramagnetic resonance spectroscopy. Cancer 95(6), 1191–1198.PubMedCrossRefGoogle Scholar
  58. Luo, J., Manning, B.D., and Cantley, L.C. (2003). Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4(4), 257–262.PubMedCrossRefGoogle Scholar
  59. Mannick, J.B., Schonhoff, C., Papeta, N., Ghafourifar, P., Szibor, M., Fang, K., and Gaston, B. (2001). S-Nitrosylation of mitochondrial caspases. J. Cell Biol. 154(6), 1111–1116.PubMedCrossRefGoogle Scholar
  60. Mao, J.H., To, M.D., Perez-Losada, J., Wu, D., Del Rosario, R., and Balmain, A. (2004). Mutually exclusive mutations of the Pten and ras pathways in skin tumor progression. Genes Dev. 18(15), 1800–1805.PubMedCrossRefGoogle Scholar
  61. Martin, J.H., Begum, S., Alalami, O., Harrison, A., and Scott, K.W. (2000). Endothelial nitric oxide synthase: correlation with histologic grade, lymph node status and estrogen receptor expression in human breast cancer. Tumour Biol. 21(2), 90–97.PubMedCrossRefGoogle Scholar
  62. McCabe, T.J., Fulton, D., Roman, L.J., and Sessa, W.C. (2000). Enhanced electron flux and reduced calmodulin dissociation may explain “calcium-independent” eNOS activation by phosphorylation. J. Biol. Chem. 275(9), 6123–6128.PubMedCrossRefGoogle Scholar
  63. Michel, T. (1999). Targeting and translocation of endothelial nitric oxide synthase. Braz. J. Med. Biol. Res. 32(11), 1361–1366.PubMedCrossRefGoogle Scholar
  64. Michell, B.J., Griffiths, J.E., Mitchelhill, K.I., Rodriguez-Crespo, I., Tiganis, T., Bozinovski, S., de Montellano, P.R., Kemp, B.E., and Pearson, R.B. (1999). The Akt kinase signals directly to endothelial nitric oxide synthase. Curr. Biol. 9, 845–848.PubMedCrossRefGoogle Scholar
  65. Mizoguchi, M., Nutt, C.L., Mohapatra, G., and Louis, D.N. (2004). Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Brain Pathol. 14(4), 372–377.PubMedCrossRefGoogle Scholar
  66. Mortensen, K., Holck, S., Christensen, I.J., Skouv, J., Hougaard, D.M., Blom, J., and Larsson, L.I. (1999a). Endothelial cell nitric oxide synthase in peritumoral microvessels is a favorable prognostic indicator in premenopausal breast cancer patients. Clin. Cancer Res. 5(5), 1093–1097.PubMedGoogle Scholar
  67. Mortensen, K.,Skouv, J., Hougaard, D.M., and Larsson, L.I. (1999b). Endogenous endothelial cell nitric-oxide synthase modulates apoptosis in cultured breast cancer cells and is transcriptionally regulated by p53. J. Biol. Chem. 274(53), 37679–37684.PubMedCrossRefGoogle Scholar
  68. Murohara, T., Asahara, T., Silver, M., Bauters, C., Masuda, H., Kalka, C., Kearney, M., Chen, D., Symes, J.F., Fishman, M.C., Huang, P.L., and Isner, J.M. (1998). Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J. Clin. Invest. 101(11), 2567–2578.PubMedCrossRefGoogle Scholar
  69. Murphy, P.R., Limoges, M., Dodd, F., Boudreau, R.T., and Too, C.K. (2001). Fibroblast growth factor-2 stimulates endothelial nitric oxide synthase expression and inhibits apoptosis by a nitric oxide-dependent pathway in Nb2 lymphoma cells. Endocrinology 142(1), 81–88.PubMedCrossRefGoogle Scholar
  70. Namkoong, S., Lee, S.J., Kim, C.K., Kim, Y.M., Chung, H.T., Lee, H., Han, J.A., Ha, K.S., and Kwon, Y.G. (2005). Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells. Exp. Mol. Med. 37(6), 588–600.PubMedGoogle Scholar
  71. Nussler, A.K., Gansauge, S., Gansauge, F., Fischer, U., Butzer, U., Kremsner, P.G., and Beger, H.G. (1998). Overexpression of endothelium-derived nitric oxide synthase isoform 3 in the vasculature of human pancreatic tumor biopsies. Langenbecks Arch. Surg. 383(6), 474–480.PubMedCrossRefGoogle Scholar
  72. O’Hayer, K.M. and Counter, C.M. (2006). A genetically defined normal somatic human cell system to study ras oncogenesis in vitro and in vivo. Methods Enzymol. 407, 637–647.PubMedCrossRefGoogle Scholar
  73. Oliveira, C.J., Schindler, F., Ventura, A.M., Morais, M.S., Arai, R.J., Debbas, V., Stern, A., and Monteiro, H.P. (2003). Nitric oxide and cGMP activate the Ras-MAP kinase pathway-stimulating protein tyrosine phosphorylation in rabbit aortic endothelial cells. Free Radic. Biol. Med. 35(4), 381–396.PubMedCrossRefGoogle Scholar
  74. Parsons, D.W., Wang, T.L., Samuels, Y., Bardelli, A., Cummins, J.M., DeLong, L., Silliman, N., Ptak, J., Szabo, S., Willson, J.K., Markowitz, S., Kinzler, K.W., Vogelstein, B., Lengauer, C., and Velculescu, V.E. (2005). Colorectal cancer: mutations in a signalling pathway. Nature 436(7052), 792.PubMedCrossRefGoogle Scholar
  75. Quintanilla, M., Brown, K., Ramsden, M., and Balmain, A. (1986). Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis. Nature 322(6074), 78–80.PubMedCrossRefGoogle Scholar
  76. Raines, K.W., Cao, G.L., Lee, E.K., Rosen, G.M., and Shapiro, P. (2006). Neuronal nitric oxide synthase-induced S-nitrosylation of H-Ras inhibits calcium ionophore-mediated extracellular-signal-regulated kinase activity. Biochem. J. 397(2), 329–336.PubMedCrossRefGoogle Scholar
  77. Rajnakova, A., Goh, P.M., Chan, S.T., Ngoi, S.S., Alponat, A., and Moochhala, S., (1997). Expression of differential nitric oxide synthase isoforms in human normal gastric mucosa and gastric cancer tissue. Carcinogenesis 18(9), 1841–1845.PubMedCrossRefGoogle Scholar
  78. Rangarajan, A., Hong, S.J., Gifford, A., and Weinberg, R.A. (2004). Species- and cell type-specific requirements for cellular transformation. Cancer Cell 6(2), 171–183.PubMedCrossRefGoogle Scholar
  79. Ridnour, L.A., Isenberg, J.S., Espey, M.G., Thomas, D.D., Roberts, D.D., and Wink, D.A. (2005). Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1. Proc. Natl. Acad. Sci. U S A 102(37), 13147–13152.PubMedCrossRefGoogle Scholar
  80. Salerno, J.C., Harris, D.E., Irizarry, K., Patel, B., Morales, A.J., Smith, S.M., Martasek, P., Roman, L.J., Masters, B.S., Jones, C.L., Weissman, B.A., Lane, P., Liu, Q., and Gross, S.S. (1997). An autoinhibitory control element defines calcium-regulated isoforms of nitric oxide synthase. J. Biol. Chem. 272(47), 29769–29777.PubMedCrossRefGoogle Scholar
  81. Samuels, Y. and Velculescu, V.E. (2004). Oncogenic Mutations of PIK3CA in Human Cancers. Cell Cycle 3(10), 1221–1224.Google Scholar
  82. Shang, Z.J., Li, Z.B., and Li, J.R. (2006). In vitro effects of nitric oxide synthase inhibitor L-NAME on oral squamous cell carcinoma: a preliminary study. Int. J. Oral Maxillofac. Surg. 35(6), 539–543.PubMedCrossRefGoogle Scholar
  83. Stallmeyer, B., Anhold, M., Wetzler, C., Kahlina, K., Pfeilschifter, J., and Frank, S. (2002). Regulation of eNOS in normal and diabetes-impaired skin repair: implications for tissue regeneration. Nitric Oxide 6(2), 168–177.PubMedCrossRefGoogle Scholar
  84. Stern, M.C. and Conti,C.J. (1996). Genetic susceptibility to tumor progression in mouse skin carcinogenesis. Prog. Clin. Biol. Res. 395, 47–55.PubMedGoogle Scholar
  85. Takahashi, M., Fukuda, K., Ohata, T., Sugimura, T., and Wakabayashi, K. (1997). Increased expression of inducible and endothelial constitutive nitric oxide synthases in rat colon tumors induced by azoxymethane. Cancer Res. 57(7), 1233–1237.PubMedGoogle Scholar
  86. Taylor, S.J., Resnick, R.J., and Shalloway, D. (2001). Nonradioactive determination of Ras-GTP levels using activated ras interaction assay. Methods Enzymol. 333, 333–342.PubMedCrossRefGoogle Scholar
  87. Tong, X. and Li, H. (2004). eNOS protects prostate cancer cells from TRAIL-induced apoptosis. Cancer Lett. 210(1), 63–71.PubMedCrossRefGoogle Scholar
  88. Tsao, H., Zhang, X., Fowlkes, K., and Haluska, F.G. (2000). Relative reciprocity of NRAS and PTEN/MMAC1 alterations in cutaneous melanoma cell lines. Cancer Res. 60(7), 1800–1804.PubMedGoogle Scholar
  89. Tschugguel, W., Knogler, W., Czerwenka, K., Mildner, M., Weninger, W., Zeillinger, R., and Huber, J.C. (1996). Presence of endothelial calcium-dependent nitric oxide synthase in breast apocrine metaplasia. Br. J. Cancer 74(9), 1423–1426.PubMedCrossRefGoogle Scholar
  90. Tse, G.M., Wong, F.C., Tsang, A.K., Lee, C.S., Lui, P.C., Lo, A.W., Law, B.K., Scolyer, R.A., Karim, R.Z., and Putti, T.C. (2005). Stromal nitric oxide synthase (NOS) expression correlates with the grade of mammary phyllodes tumour. J. Clin. Pathol. 58(6), 600–604.PubMedCrossRefGoogle Scholar
  91. Tu, Y.T., Tao, J., Liu, Y.Q., Li, Y., Huang, C.Z., Zhang, X.B., and Lin, Y. (2006). Expression of endothelial nitric oxide synthase and vascular endothelial growth factor in human malignant melanoma and their relation to angiogenesis. Clin. Exp. Dermatol. 31(3), 413–418.PubMedCrossRefGoogle Scholar
  92. Vogelstein, B. and Kinzler, K.W. (1993). The multistep nature of cancer. Trends Genet. 9(4), 138–141.PubMedCrossRefGoogle Scholar
  93. Wang, L., Shi, G.G., Yao, J.C., Gong, W., Wei, D., Wu, T.T., Ajani, J.A., Huang, S., and Xie, K. (2005). Expression of endothelial nitric oxide synthase correlates with the angiogenic phenotype of and predicts poor prognosis in human gastric cancer. Gastric Cancer 8(1), 18–28.PubMedCrossRefGoogle Scholar
  94. Weller, R., Schwentker, A., Billiar, T.R., and Vodovotz, Y. (2003). Autologous nitric oxide protects mouse and human keratinocytes from ultraviolet B radiation-induced apoptosis. Am. J. Physiol. Cell Physiol. 284(5), C1140–1148.PubMedGoogle Scholar
  95. Weninger, W., Rendl, M., Pammer, J., Mildner, M., Tschugguel, W., Schneeberger, C., Sturzl, M., and Tschachler, E. (1998). Nitric oxide synthases in Kaposi’s sarcoma are expressed predominantly by vessels and tissue macrophages. Lab. Invest. 78(8), 949–955.PubMedGoogle Scholar
  96. Xie, Q. and Nathan, C. (1994). The high-output nitric oxide pathway: role and regulation. J. Leukoc. Biol. 56(5), 576–582.PubMedGoogle Scholar
  97. Xie, Q.W., Cho, H.J., Calaycay, J., Mumford, R.A., Swiderek, K.M., Lee, T.D., Ding, A., Troso, T., and Nathan, C. (1992). Cloning and characterization of inducible nitric oxide synthase from mouse macrophages. Science 256(5054), 225–228.PubMedCrossRefGoogle Scholar
  98. Yagihashi, N., Kasajima, H., Sugai, S., Matsumoto, K., Ebina, Y., Morita, T., Murakami, T., and Yagihashi, S. (2000). Increased in situ expression of nitric oxide synthase in human colorectal cancer. Virchows Archiv 436(2), 109–114.PubMedCrossRefGoogle Scholar
  99. Ying, L. and Hofseth, L.J. (2007). An emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Cancer Res. 67(4), 1407–1410.PubMedCrossRefGoogle Scholar
  100. Zaragoza, C., Soria, E., Lopez, E., Browning, D., Balbin, M., Lopez-Otin, C., and Lamas, S. (2002). Activation of the mitogen activated protein kinase extracellular signal-regulated kinase 1 and 2 by the nitric oxide-cGMP-cGMP-dependent protein kinase axis regulates the expression of matrix metalloproteinase 13 in vascular endothelial cells. Mol. Pharmacol. 62(4), 927–935.PubMedCrossRefGoogle Scholar
  101. Zeillinger, R., Tantscher, E., Schneeberger, C., Tschugguel, W., Eder, S., Sliutz, G., and Huber, J.C. (1996). Simultaneous expression of nitric oxide synthase and estrogen receptor in human breast cancer cell lines. Breast Cancer Res. Treat. 40(2), 205–207.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Pharmacology and Cancer Biology, Department of Radiation OncologyDuke University Medical CenterDurhamUSA

Personalised recommendations