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. © 2016 Elsevier B.V.

This study explores the V600BRAF-MITF-PGC-1αaxis and comparesmetabolic 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.

New insight into the role of metabolic reprogramming in melanoma cells harboring BRAF mutations / Ferretta, A.; Maida, I.; Guida, Stefania; Azzariti, A.; Porcelli, L.; Tommasi, S.; Zanna, P.; Cocco, T.; Guida, M.; Guida, G.. - In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH. - ISSN 0167-4889. - 1863:11(2016), pp. 2710-2718. [10.1016/j.bbamcr.2016.08.007]

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

GUIDA, STEFANIA;
2016

Abstract

This study explores the V600BRAF-MITF-PGC-1αaxis and comparesmetabolic 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.
2016
16-ago-2016
1863
11
2710
2718
New insight into the role of metabolic reprogramming in melanoma cells harboring BRAF mutations / Ferretta, A.; Maida, I.; Guida, Stefania; Azzariti, A.; Porcelli, L.; Tommasi, S.; Zanna, P.; Cocco, T.; Guida, M.; Guida, G.. - In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH. - ISSN 0167-4889. - 1863:11(2016), pp. 2710-2718. [10.1016/j.bbamcr.2016.08.007]
Ferretta, A.; Maida, I.; Guida, Stefania; Azzariti, A.; Porcelli, L.; Tommasi, S.; Zanna, P.; Cocco, T.; Guida, M.; Guida, G.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1125382
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