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

Anna Ferretta, Immacolata Maida, Stefania Guida, Amalia Azzariti, Letizia Porcelli, Stefania Tommasi, Paola Zanna, Tiziana Cocco, Michele Guida, Gabriella Guida

Research output: Contribution to journalArticle

Abstract

This study explores the V600BRAF-MITF-PGC-1α axis and compares metabolic and functional changes occurring in primary and metastatic V600BRAF melanoma cell lines. V600BRAF mutations in homo/heterozygosis were found to be correlated to high levels of pERK, to downregulate PGC-1α/β, MITF and tyrosinase activity, resulting in a reduced melanin synthesis as compared to BRAFwt melanoma cells. In this scenario, V600BRAF switches on a metabolic reprogramming in melanoma, leading to a decreased OXPHOS activity and increased glycolytic ATP, lactate, HIF-1α and MCT4 levels. Furthermore, the induction of autophagy and the presence of ER stress markers in V600BRAF metastatic melanoma cells suggest that metabolic adaptations of these cells occur as compensatory survival mechanisms. For the first time, we underline the 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 a reduction of basal autophagy could be suitable targets for novel combination therapies in a specific subgroup of metastatic melanoma.

Original languageEnglish
Pages (from-to)2710-2718
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1863
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

Keywords

  • BRAF
  • Lactate
  • MCT4
  • Melanoma
  • peIF2α
  • PGC-1α

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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