Mcl-1 cleavage and sustained phosphorylation of c-Jun-N-terminal kinase mediate melanoma apoptosis induced by 2-acetyl furanonaphthoquinone: roles of Bcl-2 and p53.
2-acetyl furanonaphthoquinone (FNQ) is a naturally occurring drug with enhanced toxicity versus glucose-starved tumor cells, which frequently show topoisomerase II drug resistance. Since loss of p53 tumor suppressor function or overexpression of the anti-apoptotic bcl-2 gene can decrease susceptibility to some cancer therapies, we now investigated the effect of FNQ against genetically matched C8161 melanoma cell lines transduced to express unequal levels of Bcl-2, or engineered to harbour a functional wt p53 for comparison with dominant-negative mutant p53 R175H. Cells with differing p53 genotype showed susceptibility to FNQ. However, this response was attenuated in those overexpressing mutant p53, although a brief p53 induction was early seen in FNQ-treated wt p53 cells. Cells susceptible to FNQ showed cleavage of anti-apoptotic Mcl-1, sustained activation of the c-Jun N-terminal Kinase (p-JNK), and apoptosis-associated PARP fragmentation, all of which were counteracted in bcl-2 overexpressing cells. Suppression of JNK activation with the specific inhibitor, SP600125 also prevented FNQ-mediated cell death. Our data suggests that Bcl-2, persistent JNK phosphorylation and cleavage of anti-apoptotic Mcl-1 are key events controlling susceptibility to FNQ.
Rieber
Manuel
M
Instituto Venezolano de Investigaciones Científicas, IVIC, Centre for Microbiology & Cell Biology, Laboratory of Tumor Cell Biology, Caracas, Venezuela. mrieber@ivic.ve
Rieber
Mary Strasberg
MS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009285:Naphthoquinones / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
C508754:2-acetylfuranonaphthoquinone; D000970:Antineoplastic Agents; D005663:Furans; D009285:Naphthoquinones; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D048056:Mitogen-Activated Protein Kinase 9; D020169:Caspases