Oncogenic BRAF signalling increases Mcl-1 expression in cutaneous metastatic melanoma.

The Bcl-2 family member Mcl-1 is essential for melanoma survival; however, the influence of oncogenic BRAF signalling remains elusive. In this study, Mcl-1 splice variant expression was determined in a panel of melanoma cell lines in relation to BRAF mutational status. Mcl-1 L m RNA expression was increased in melanoma cells compared with primary melanocytes with significantly increased m RNA and protein expression observed in BRAF V600E mutant melanoma cells. Although no change in Mcl-1S m RNA was observed, Mcl-1 S protein expression also increased in BRAF mutant melanoma cells. Additionally, while over-expression of mutant BRAFV600E increased both Mcl-1 L and Mcl-1 S expression, inhibition of hyperactive BRAF signalling resulted in decreased Mcl-1 L expression. These studies suggest that the regulation of Mcl-1 expression by BRAF signalling is increased by oncogenic activation of BRAF, revealing a mechanism of apoptotic resistance which may be overcome by the use of more specifically targeted Mcl-1 inhibitors. [ABSTRACT FROM AUTHOR]