Down-regulation of tumor necrosis factor alpha expression by activating transcription factor 2 increases UVC-induced apoptosis of late-stage melanomacells

To identify mechanisms whereby activating transcription factor 2 (ATF2) alt ers the radiation resistance of human melanoma cells, we examined the possi ble role of ATF2 in WC-induced apoptosis. Forced expression of full-length or truncated (Delta 1-195 amino acids) forms of ATF2 in LU1205, a late-stag e human melanoma cell line, elevated the levels of UVC-induced apoptosis. A t the same time, either truncated or full-length forms of ATF2 reduced UVC- induced activation of the tumor necrosis factor-alpha (TNF alpha) promoter and decreased expression of TNF alpha. Forced expression of c-Jun in ATF2-e xpressing melanoma cells restored TNF alpha expression, suggesting that bot h forms of ATF2 sequestered transcription factors that positively regulate TNF alpha expression in response to UV irradiation. Antagonistic antibodies to Fas, but not to TNFR1, efficiently suppressed UVC-induced apoptosis, su ggesting that the Fas pathway mediates the primary apoptotic signal in mela noma cells whereas the TNFR1 pathway elicits a survival signal. Indeed, tre atment of melanoma cells with TNF alpha before UVC irradiation partially su ppressed WC-induced apoptosis, further supporting the protective role of TN F alpha in UVC-treated melanoma cells. Taken together, our findings suggest that ATF2 contributes to UVC-induced apoptosis through transcriptional sil encing of TNF alpha, which balances Fas-mediated cell death in melanoma.