Titre :

Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors

Auteur(s) :

Khamari, Raeeka [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Trinh, Anne [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Gabert, Pierre Elliott [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Corazao-Rozas, Paola [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Riveros-Cruz, Samuel [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Balayssac, Stéphane [Auteur]
Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique [SPCMIB]
Malet-Martino, Myriam [Auteur]
Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique [SPCMIB]
Dekiouk, Salim [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Joncquel Chevalier Curt, Marie [Auteur]
Maboudou, Patrice [Auteur]
Garçon, Guillaume [Auteur]
Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS]
Ravasi, Laura [Auteur]
Institut de médecine predictive et de recherche thérapeutique [IMPRT]
Guerreschi, Pierre [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Mortier, Laurent [Auteur]
Thérapies Assistées par Lasers et Immunothérapies pour l'Oncologie - U 1189 [OncoThAI]
Quesnel, Bruno [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Marchetti, Philippe [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Kluza, Jerome [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]

Titre de la revue :

Cell Death and Disease

Pagination :

325

Éditeur :

Nature Publishing Group

Date de publication :

2018

ISSN :

2041-4889

Discipline(s) HAL :

Sciences du Vivant [q-bio]/Cancer
Sciences du Vivant [q-bio]/Biologie cellulaire/Organisation et fonctions cellulaires [q-bio.SC]
Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Dermatologie
Sciences du Vivant [q-bio]/Sciences pharmaceutiques/Pharmacologie

Résumé en anglais : [en]

Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic ...
Lire la suite >Targeted therapies as BRAF and MEK inhibitor combination have been approved as first-line treatment for BRAF-mutant melanoma. However, disease progression occurs in most of the patients within few months of therapy. Metabolic adaptations have been described in the context of acquired resistance to BRAF inhibitors (BRAFi). BRAFi-resistant melanomas are characterized by an increase of mitochondrial oxidative phosphorylation and are more prone to cell death induced by mitochondrial-targeting drugs. BRAFi-resistant melanomas also exhibit an enhancement of oxidative stress due to mitochondrial oxygen consumption increase. To understand the mechanisms responsible for survival of BRAFi-resistant melanoma cells in the context of oxidative stress, we have established a preclinical murine model that accurately recapitulates in vivo the acquisition of resistance to MAPK inhibitors including several BRAF or MEK inhibitors alone and in combination. Using mice model and melanoma cell lines generated from mice tumors, we have confirmed that the acquisition of resistance is associated with an increase in mitochondrial oxidative phosphorylation as well as the importance of glutamine metabolism. Moreover, we have demonstrated that BRAFi-resistant melanoma can adapt mitochondrial metabolism to support glucose-derived glutamate synthesis leading to increase in glutathione content. Besides, BRAFi-resistant melanoma exhibits a strong activation of NRF-2 pathway leading to increase in the pentose phosphate pathway, which is involved in the regeneration of reduced glutathione, and to increase in xCT expression, a component of the xc—amino acid transporter essential for the uptake of cystine required for intracellular glutathione synthesis. All these metabolic modifications sustain glutathione level and contribute to the intracellular redox balance to allow survival of BRAFi-resistant melanoma cells.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Collections :

• Thérapies Lasers Assistées par l'Image pour l'Oncologie (ONCO-THAI) - U1189

Source :

Harvested from HAL