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

Abstract

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.