title: New insight into the role of metabolic reprogramming in melanoma cells harboring BRAF mutations.
abstract: This study explores theV600BRAF-MITF-PGC-1α axis and compares metabolic and functional changes occurring in primary and metastaticV600BRAF 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 inV600BRAF 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.
authors.affiliation: Department of Basic Medical Sciences Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ferretta
authors.affiliation: Department of Basic Medical Sciences Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Maida
authors.affiliation: Dermatology Unit, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Guida
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.affiliation: Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.affiliation: Molecular Genetics Laboratory and Radiology, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Tommasi
authors.affiliation: Department of Basic Medical Sciences Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Zanna
authors.affiliation: Department of Basic Medical Sciences Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cocco
authors.affiliation: Medical Oncology Department, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy. Electronic address: micguida@libero.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Guida
authors.affiliation: Department of Basic Medical Sciences Neurosciences and Sense Organs, University of Bari, Bari, Italy. Electronic address: gabriella.guida@uniba.it.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Guida
mesh_terms: D001343:Autophagy; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004734:Energy Metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006019:Glycolysis; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics* / Q000556:secondary; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009154:Mutation; D009362:Neoplasm Metastasis; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D015852:Eukaryotic Initiation Factor-2; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C486497:PPARGC1A protein, human; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins; D000242:Cyclic AMP; D014442:Monophenol Monooxygenase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: BRAF; Lactate; MCT4; Melanoma; PGC-1α; peIF2α