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

This study explores the V600BRAF-MITF-PGC-1αaxis and comparesmetabolic and functional changes occurring inprimary and metastatic V600BRAF melanoma cell lines.V600BRAF mutations in homo/heterozygosis were found to be correlated to high levels of pERK, to downregulatePGC-1α/β, MITF and tyrosinase activity, resulting in a reduced melanin synthesis as compared to BRAFwtmelanoma cells. In this scenario, V600BRAF switches on a metabolic reprogramming in melanoma, leading to adecreased OXPHOS activity and increased glycolytic ATP, lactate, HIF-1α and MCT4 levels. Furthermore, theinduction of autophagy and the presence of ER stress markers in V600BRAF metastatic melanoma cells suggest thatmetabolic adaptations of these cells occur as compensatory survival mechanisms. For the first time, we underlinethe role of peIF2α as an important marker of metastatic behaviour in melanoma.Our results suggest the hypothesis that inhibition of the glycolytic pathway, inactivation of peIF2α and areduction of basal autophagy could be suitable targets for novel combination therapies in a specific subgroupof metastatic melanoma.