PGC-1α in melanoma: a key factor for antioxidant response and mitochondrial function

Abstract

Melanocortin 1 receptor (MC1R) and BRAF are common mutations in melanoma. Through different pathways, they each regulate the expression of PGC-1α, which is a key factor in the regulation of mitochondrial biogenesis and the antioxidant response. Our aim was to study the importance of the different regulatory characteristics of MC1R and BRAF on the pathways they regulate in melanoma. For this purpose, ROS production, levels of gene expression and enzymatic activities were analyzed in HBL and MeWo, with wild-type MC1R and BRAF, and A375 cells with mutant MC1R and BRAF. HBL cells showed a functional MC1R-PGC-1α pathway and exhibited the lowest ROS production, probably because of a better mitochondrial pool and the presence of UCP2. On the other hand, MeWo cells showed elevated levels of PGC-1α but also high ROS production, similar to the A375 cells, along with an activated antioxidant response and significantly low levels of UCP2. Finally, A375 cells are mutant for BRAF, and thus showed low levels of PGC-1α. Consequently, A375 cells exhibited poor mitochondrial biogenesis and function, and no antioxidant response. These results show the importance of the activation of the MC1R-PGC-1α pathway for mitochondrial biogenesis and function in melanoma development, as well as BRAF for the antioxidant response regulated by PGC-1α