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Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors

2016; Impact Journals LLC; Volume: 7; Issue: 26 Linguagem: Inglês

10.18632/oncotarget.7790

1949-2553

Paola Corazao-Rozas, P. Guerreschi, Fanny André, Pierre-Elliott Gabert, Steve Lancel, Salim Dekiouk, Delphine Fontaine, Meryem Tardivel, Ariel Savina, Bruno Quesnel, Laurent Mortier, Philippe Marchetti, Jérôme Kluza,

Protein Tyrosine Phosphatases

// Paola Corazao-Rozas 1, 2, 3, * , Pierre Guerreschi 1, 2, 3, * , Fanny André 1, 2, 3 , Pierre-Elliott Gabert 1, 2, 3 , Steve Lancel 4 , Salim Dekiouk 1, 2, 3 , Delphine Fontaine 1, 2, 3 , Meryem Tardivel 6 , Ariel Savina 7 , Bruno Quesnel 1, 2, 3 , Laurent Mortier 1, 2, 3 , Philippe Marchetti 1, 2, 3, 5, # , Jérome Kluza 1, 2, 3, # 1 University Lille, Inserm, CHU Lille, UMR-S 1172 - JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Lille, France 2 Institut pour la Recherche sur le Cancer de Lille (IRCL), Lille, France 3 SIRIC OncoLille, Lille, France 4 University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, Lille, France 5 Centre de Bio-Pathologie, Plate-forme de Biothérapie, Banque de Tissus, CHRU Lille, Lille, France 6 Bioimaging Center, Lille Nord de France-Campus HU, Université de Lille 2, Lille, France 7 Institut Roche, Boulogne-Billancourt, France * These authors contributed equally to this work # These authors shared equally co-ownership to this work Correspondence to: Jérome Kluza, email: jerome.kluza@inserm.fr Philippe Marchetti, email: philippe.marchetti@inserm.fr Keywords: vemurafenib, cobimetinib, BRAF, Ca2+ uptake, melanoma Received: November 05, 2015 Accepted: February 05, 2016 Published: February 29, 2016 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.