Oral communication, iL35

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Chemoprevention of melanoma progression mediated by NO/neural NO synthase (nNOS), an accelerator of the transformation process

SPEAKER F.L. Meyskens #whois submiter ?
AUTHOR(s) F.L. Meyskens, S. Yang, T. Poulos, H. Ji, R.B. Silverman

Our laboratory has been extensively involved in the study of abnormal redox status and redox-sensitive signalings such as AP-1, NF-κB and more recently APE/Ref-1. Our overall goal is to identify key factors underlying melanoma development that can be exploited for therapeutic intent. It has been well-documented that UVR exposure, especially sunburn at a young age, is particularly linked to melanoma incidence. As an important environmental carcinogen, UVR not only generates ROS, but also produces a large amount of nitric oxide (NO) in human skin. Utilizing a NO-donor (DETA) to mimic NO stress, we demonstrated that melanoma proliferation and invasion potential were significantly stimulated by and associated with induction of many proteins involved in cell growth (c-Jun, JunD), anti-apoptosis (Bcl-2, APE/Ref-1) and metastasis signalings (MMP-1, Snail). Notably, long-term exposure of DETA/NO stress resulted in over-growth of primary normal human melanocytes with formation of foci in in vitro culture, indicating gain of additional vertical growth potential. As melanocytes originate from the neural crest, we propose that neural NO synthase (nNOS) plays an important role in generating NO and mediating NO stress in human melanoma. Both our in vitro cell culture (Immunoblotting) and in vivo human biopsy (Immunohistochemistry) studies demonstrated marked elevation of nNOS expressions in melanoma cells. More interestingly, induction of nNOS and elevated NO levels were evident after UV-B radiation or incubation with bFGF. Knockdown of nNOS with siRNA efficiently reduced the DETA-induced melanoma proliferation and invasion potential, with marked reduction of c-Jun, Bcl-2 and MMP-1. A novel synthesized nNOS inhibitor (JI-11) was utilized to inhibit nNOS activity; our data showed that co-treatment of JI-11(1μM) significantly attenuated the alterations induced by UV-B radiation and DETA/NO treatment. We have tested a series of novel synthesized nNOS inhibitors representing a varied range of structures and distinct potentials and enzyme selectivity. The nNOS selectivity of Ki/nNOS values (but not Ki/iNOS or Ki/eNOS) were statistically significantly correlated with their observed anti-melanoma potency and anti-invasion activity, indicating that the inhibition of nNOS is crucial for reducing melanoma invasion. Through extensive structure-activity analysis and chemical modification, we are improving the bioavailability and anti-melanoma potential of nNOS inhibitors. Based on our studies, we propose that targeting nNOS with application of specific synthetic inhibitors to diminish NO stress represents an innovative and promising strategy for the chemoprevention of cutaneous melanoma.



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Université de Bordeaux 2 & Conseil Régional Aquitaine