New insight into the role of metabolic reprogramming in melanoma cells harboring BRAF mutations

This study explores the (V600)BRAF-MITF-PGC-1 alpha axis and compares metabolic and functional changes occurring in primary and metastatic (V600)BRAF melanoma cell lines. (V600)BRAF mutations in homo/heterozygosis were found to be correlated to high levels of pERK, to downregulate PGC-1 alpha/beta, MITF and tyrosinase activity, resulting in a reduced melanin synthesis as compared to BRAFwt melanoma cells. In this scenario, (V600)BRAF switches on a metabolic reprogramming in melanoma, leading to a decreased OXPHOS activity and increased glycolytic ATP, lactate, HIF-1 alpha and MCT4 levels. Furthermore, the induction of autophagy and the presence of ER stress markers in (V600)BRAF metastatic melanoma cells suggest that metabolic adaptations of these cells occur as compensatory survival mechanisms. For the first time, we underline the role of peIF2 alpha as an important marker of metastatic behaviour in melanoma. Our results suggest the hypothesis that inhibition of the glycolytic pathway, inactivation of pelF2a and a reduction of basal autophagy could be suitable targets for novel combination therapies in a specific subgroup of metastatic melanoma. (C) 2016 Elsevier B.V. All rights reserved.