Regulation of the Bcl-2 family members Bim, PUMA and Mcl-1 by MEK/ERK signaling plays a critical role in survival of melanoma cells

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Although the MEK/ERK pathway is known to play an important role in melanoma cell survival, the mechanism(s) by which it does so is not fully understood. We report in this study that inhibition of MEK induces apoptosis in the majority of melanoma cell lines through a mitochondria-mediated pathway that is inhibitable by over-expression of Bcl-2. Induction of apoptosis by the MEK inhibitor U0126 was associated with activation of Bax and Bak, release of mitochondrial apoptogenic proteins, activation of caspase-3 and cleavage of its substrate PARP. However, the caspase cascade did not appear to be indispensable in apoptosis induced by inhibition of MEK. Instead, AIF played a crucial role in that inhibition of AIF by siRNA blocked U0126-induced apoptosis. The MEK/ERK pathway is required for survival of a proportion of melanoma cells, in which the pro-apoptotic Bcl-2 family members Bim and PUMA are inhibited at the transcriptional and post-translational levels. Moreover, activation of MEK/ERK is necessary for transcription of the anti-apoptotic Bcl-2 family member Mcl-1 in melanoma cells whose survival is dependent on activation of this pathway, but inhibition of MEK increases Mcl-1 transcription in cells whose survival is minimally affected. Therefore, MEK/ERK-mediated survival of melanoma cells is controlled, at least in part, by regulation of the pro- or anti-survival Bcl-2 family members Bim, PUMA, and Mcl-1. Our results suggest that co-targeting Mcl-1 and the MEK/ERK pathway is worthy of further investigation for development of targeted therapy in treatment of melanoma.