Abstract 4200: Interaction between mPGES-1 and iNOS promotes human melanoma progression

Abstract

Abstract Melanoma cells in vivo are well known to express varying inflammatory features, which is not limited by somatic mutational subclass. Among the most prevalent of inflammatory markers are iNOS (inducible Nitric Oxide Synthase) generated NO production and COX-2/PGE2, and for which their active pathways have been shown to enhance carcinogenesis and tumor progression, stimulate angiogenesis, support tumor growth, and promote metastasis. COX-2 inhibitors are well studied agents that inhibit tumor growth and prevent tumor development including melanoma, but the focus of research has shifted to develop inhibitors for enzymes, which are downstream of COX-2, especially microsomal PGE2 synthase-1 (mPGES-1), due to the cardiovascular risk associated with the initial COX-2 inhibitory drugs. Here, we demonstrate crosstalk between iNOS/NO and mPGES-1/PGE2 signaling pathways and suggest that mPGES-1 is a novel potential therapeutic target in human melanoma employing a spectrum of well-defined human cell lines, as well as human tissues. Our melanoma stage III survival Tissue MicroArray analysis shows that the expression of mPGES-1 is elevated in 65% of human stage III melanomas and intense expression of mPGES-1 is significantly associated with the short-term survival of patients. More interestingly, about 90 % of patient samples which express mPGES-1 were also positive for iNOS. In addition, treatment of human melanoma cells with NO donors or constitutively-driven expression of iNOS resulted in increased PGE2 production, which was suppressed by mPGES-1 inhibition, indicating that the pathway is active and targetable. Moreover, iNOS was found to interact directly with mPGES-1, and iNOS or NO donors enhance mPGES-1 activity in melanoma cells and in vitro, suggesting that iNOS-mediated NO promotes PGE2 production through mPGES-1 activation. mPGES-1 inhibition by its shRNA or specific inhibitors suppressed human melanoma cell viability and migration. Collectively, these findings suggest that the interaction between iNOS and mPGES-1 is associated with human melanoma progression and could be considered as a novel target for translational application in melanoma growth regulation. Citation Format: Sun-Hee Kim, Yuuri Hashimoto, Suhendan Ekmekcioglu, Elizabeth A. Grimm. Interaction between mPGES-1 and iNOS promotes human melanoma progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4200. doi:10.1158/1538-7445.AM2014-4200