p38 protects human melanoma cells from UV-induced apoptosis through down-regulation of NF-kappa B activity and Fas expression

Identifying mechanisms that underlie the resistance of human melanoma to ra diation and chemotherapy is expected to assist in developing new strategies for the treatment of this tumor type. We recently demonstrated that throug h up-regulation of TNF alpha, ATF2 increases the resistance of late stage m elanoma cells to apoptosis induced by UV-irradiation, In elucidating the ro le of ATF2 kinases, we now demonstrate that ASK1/MKK6/p38 elicits suppressi on of Fas expression. ASK1/p38 downregulates the expression of a Fas via NF -kappa B/SP1 site on the Fas promoter. Deletion or mutation of NF-kappa B/S P1 within the Fas promoter abrogates p38 effect. ASK1/p38 silences the Fas promoter by inhibition of I kappa B alpha phosphorylation - thereby limitin g NF-kappa B activity. Forced expression of a dominant negative form of p38 (p38-ASP) or treatment with p38 pharmacological inhibitor, SB203580, incre ases NF-kappa B activity, Fas expression and the levels of UVC-induced apop tosis in late stage melanoma cells. Inhibition of p38 activity also restore d NF-kappa B activity and Fas expression in early-phase melanoma cells, sug gesting that p38 elicited suppression of Fas expression is not restricted t o late phase melanoma, Identifying p38-mediated down-regulation of Fas expr ession illustrates a novel regulatory pathway by which ASK1/MKK6/p38 alters the degree and nature of the UV-induced apoptosis of melanoma cells.