Arsenite sensitizes human melanomas to apoptosis via tumor necrosis factor alpha-mediated pathway.
Arsenic is a well established human carcinogen and is associated with a variety of cancers including those of the skin. Paradoxically, arsenic has also been used, amid at low doses, in the treatment of leukemia for over a century. Here we demonstrate that low to moderate concentrations of arsenite (2-10 microm) that has little or no effect on normal melanocytes may induce apoptosis of human melanomas including highly metastatic ones despite their low surface Fas levels. The two prerequisites that dictate apoptotic response of melanomas upon arsenite treatment are low nuclear NF-kappaB activity and an endogenous expression of tumor necrosis factor alpha. Under these conditions, melanoma cells acquired sensitivity to tumor necrosis factor alpha-mediated killing. On the other hand, signaling pathways including those of phosphatidylinositol 3-kinase-AKT, MEK-ERK, and JNK play a protective role against arsenite-induced oxidative stress and apoptosis in melanoma cells. Suppression of these pathways dramatically accelerates arsenite-induced apoptosis. Taken together, these data could provide potential approaches to sensitize melanomas to the cytotoxic effects of arsenite through modulating the signaling pathways.
Ivanov
Vladimir N
VN
Center for Radiological Research, College of Physicians and Surgeons, Mailman School of Public Health, Columbia University, New York, New York 10032, USA. vni3@columbia.edu
Hei
Tom K
TK
D000818:Animals; D017209:Apoptosis; D018053:Arsenites / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis
D018053:Arsenites; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D008156:Luciferases; C015001:arsenite