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 important role in the resistance of melanoma to radiation and chemotherapy. Whereas ATF2 up-regulates the expression of tumor necrosis factor alpha, which serves as a survival factor in late-stage melanoma cells, p38 attenuates Fas expression via inhibition of nuclear factor-kappaB. We investigated whether ATF2-derived peptides could be used to alter the sensitivity of human melanoma cells to radiation and chemical treatment. Of four 50-amino acid peptides tested, the peptide spanning amino acids 50-100 elicited the most efficient increase in the sensitivity of human melanoma cells to UV radiation or treatment by mitomycin C, Adriamycin, and verapamil, or UCN-01, as revealed by apoptosis assays. Sensitization by ATF2 peptide was also observed in the MCF7 human breast cancer cells but not in early-stage melanoma or melanocytes, or in in vitro-transformed 293T cells. When combined with an inhibitor of p38 catalytic activity, cells expressing amino acids 50-100 of ATF2 exhibited an increase in the degree of programmed cell death, indicating that combined targeting of ATF2 and p38 kinases is sufficient to induce apoptosis in late-stage melanoma cells. The ability of the peptide to increase apoptosis coincided with increased cell surface expression of Fas, which is the primary death-signaling cascade in these late-stage melanoma cells. Overall, our studies identified a critical domain of ATF2 that may be used to sensitize tumor cells to radiation and chemical treatment-induced apoptosis and that can induce apoptosis when combined with inhibition of ATF2 kinase, p38.
Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
A
A
Bhoumik
V
V
Ivanov
Z
Z
Ronai
D051698:Activating Transcription Factor 2; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D053613:Janus Kinase 1; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011836:Radiation Tolerance / Q000187:drug effects*; D014157:Transcription Factors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000970:Antineoplastic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010446:Peptide Fragments; D014157:Transcription Factors; D019014:fas Receptor; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases