Activating transcription factor 2-derived peptides alter resistance of human tumor cell lines to ultraviolet irradiation and chemical treatment

Activating transcription factor 2 (ATF2) and its kinase, p38, play an impor tant role in the resistance of melanoma to radiation and chemotherapy, Wher eas ATF2 up-regulates the expression of tumor necrosis factor a, which serv es as a survival factor in late-stage melanoma cells, p38 attenuates Fas ex pression via inhibition of nuclear factor-KB, We investigated whether ATF2- derived peptides could be used to alter the sensitivity of human melanoma c ells to radiation and chemical treatment. Of four 50-amino acid peptides te sted, the peptide spanning amino acids 50-100 elicited the most efficient i ncrease in the sensitivity of human melanoma cells to UV radiation or treat ment by mitomycin C, Adriamycin, and verapamil, or UCN-01, as revealed by a poptosis assays. Sensitization by ATF2 peptide was also observed in the MCF 7 human breast cancer cells but not in early-stage melanoma or melanocytes, or in ill vitro-transformed 293T cells. When combined with an inhibitor of p38 catalytic activity, cells expressing amino acids 50-100 of ATF2 exhibi ted an increase in the degree of programmed cell death, indicating that com bined targeting of ATF2 and p38 kinases is sufficient to induce apoptosis i n late-stage melanoma cells. The ability of the peptide to increase apoptos is coincided with increased cell surface expression of Fas, which is the pr imary death-signaling cascade in these late-stage melanoma cells. Overall, our studies identified a critical domain of ATF2 that may be used to sensit ize tumor cells to radiation and chemical treatment-induced apoptosis and t hat can induce apoptosis when combined with inhibition of ATF2 kinase, p38.