Abstract 5466: nNOS, a novel target for melanoma prevention and therapy

Abstract

Abstract It is well recognized that nitric oxide (NO) is involved in tumor progression, including human melanoma. Our data showed that NO stress by NO donor DETA treatment remarkably stimulated the proliferation of normal primary melanocytes with foci formed in culture and the metastatic capacity of human melanoma cells detected by matrigel invasion assays was also significantly induced with DETA incubation. Our previous mechanistic studies have revealed that NO-induced melanoma progression is mediated by Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1), which plays an important role in melanomagenesis and development, in a feed-forward loop manner. Both our in vitro cell culture (Immunoblotting) and in vivo human biopsy (Immunohistochemistry) studies have demonstrated the predominant elevations of nNOS expression levels in melanoma cells. Notably, induction of nNOS was evident with UVB radiation and growth factor bFGF treatments. Knockdown of nNOS with siRNA efficiently reduced the DETA-induced melanoma proliferation and invasion potential, and was associated with reductions of many genes that related to proliferation, anti-apoptosis and invasion, such as c-Jun, Bcl-2, and MMP-1. A novel synthesized nNOS inhibitor JI-11 was utilized to inhibit nNOS activity and our data showed that co-treatment of JI-11 at 1uM concentration significantly attenuated the alterations induced by UVB radiation and DETA treatments. MTS analysis also revealed that pretreatment of JI-11 sensitized melanoma cells to chemo-drug Cisplatin. We hypothesize that targeting nNOS/NO to prevent and treat melanoma is innovative and potentially of great benefit. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5466.