title: Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors.
abstract: Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER-mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Corazao-Rozas
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Guerreschi
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: André
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.
authors.forename: Pierre-Elliott
authors.initials: PE
authors.lastname: Gabert
authors.affiliation: University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, Lille, France.
authors.forename: Steve
authors.initials: S
authors.lastname: Lancel
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.
authors.forename: Salim
authors.initials: S
authors.lastname: Dekiouk
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Fontaine
authors.affiliation: Bioimaging Center, Lille Nord de France-Campus HU, Université de Lille 2, Lille, France.
authors.forename: Meryem
authors.initials: M
authors.lastname: Tardivel
authors.affiliation: Institut Roche, Boulogne-Billancourt, France.
authors.forename: Ariel
authors.initials: A
authors.lastname: Savina
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mortier
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.|Centre de Bio-Pathologie, Plate-forme de Biothérapie, Banque de Tissus, CHRU Lille, Lille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France.|Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France.|SIRIC OncoLille, Lille, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Kluza
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001384:Azetidines / Q000494:pharmacology; D002118:Calcium / Q000737:chemistry; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology; D016896:Treatment Outcome; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D007211:Indoles; D024101:Mitochondrial Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C574276:cobimetinib; D002118:Calcium
keywords: BRAF; Ca2+ uptake; cobimetinib; melanoma; vemurafenib