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

Abstract

Identifying mechanisms that underlie the resistance of human melanoma to radiation and chemotherapy is expected to assist in developing new strategies for the treatment of this tumor type. We recently demonstrated that through up-regulation of TNFa, ATF2 increases the resistance of late stage melanoma cells to apoptosis induced by UV-irradiation. In elucidating the role of ATF2 kinases, we now demonstrate that ASK1/MKK6/ p38 elicits suppression of Fas expression. ASK1/p38 downregulates the expression of a Fas via NF-kB/SP1 site on the Fas promoter. Deletion or mutation of NFkB/SP1 within the Fas promoter abrogates p38 e ect. ASK1/p38 silences the Fas promoter by inhibition of IkBa phosphorylation ± thereby limiting NF-kB activity. Forced expression of a dominant negative form of p38 (p38-ASP) or treatment with p38 pharmacological inhibitor, SB203580, increases NF-kB activity, Fas expression and the levels of UVC-induced apoptosis in late stage melanoma cells. Inhibition of p38 activity also restored NF-kB activity and Fas expression in earlyphase melanoma cells, suggesting that p38 elicited suppression of Fas expression is not restricted to late phase melanoma. Identifying p38-mediated down-regulation of Fas expression illustrates a novel regulatory pathway by which ASK1/MKK6/p38 alters the degree and nature of the UV-induced apoptosis of melanoma cells.

Carbon Monoxide Differentially Modulates STAT1 and STAT3 and Inhibits Apoptosis via a Phosphatidylinositol 3-Kinase/Akt and p38 Kinase-dependent STAT3 Pathway during Anoxia-Reoxygenation Injury

“…Furthermore, p38 MAPK has been shown to protect human melanoma cells from UV-induced apoptosis through the down-regulation of Fas expression (25). Given that our current studies demonstrate that the activation of p38 MAPK is via PI3K/Akt (Fig.…”

Cellular response to oxidative stress: Signaling for suicide and survival*

“…Such an approach has yielded evidence for both pro-apoptotic (Bulavin et al, 1999;Shimizu et al, 1999;Zhuang et al, 2000;Gratton et al, 2001) as well as anti-apoptotic (Nemoto et al, 1998;Ivanov and Ronai, 2000) functions of these kinases. In addition, although many studies have correlated p38 activation with oxidative stress-induced apoptosis, in some of these circumstances, inhibiting the kinase through use of pharmacologic inhibitors does not alter the apoptosis (Wang et al, , 2000a.…”

Functions of epidermal growth factor receptor in cisplatin response of thyroid cells

“…For example, studies have suggested that over expressing an active form of the p38/MAPK activator MKK6 protects cardiac myocytes from treatment with anisomyc [42]. Similarly, early activation of p38/MAPK is necessary and sufficient to protect Kym cells from tumour necrosis factor-α-mediated apoptosis [43], and expression of the p38/MAPK attenuates cell death induced by Fas ligand and UV light [44]. There are even more reports concerning a proapoptotic function of p38/MAPK: it is proapoptotic in apoptosis induced by withdrawal of trophic factors [45], glutamate [46], and sodium salicylate [47].…”