Title :

Glucose metabolism and nrf2 coordinate the antioxidant response in melanoma resistant to mapk inhibitors

Author(s) :

Khamari, Raeeka [Auteur]
Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172
Trinh, Anne [Auteur]
Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290
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, Stephane [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 (JPArc) - U1172
Joncquel-Chevalier Curt, Marie [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Maboudou, Patrice [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Garçon, Guillaume [Auteur]
IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483
IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483
Ravasi, Laura [Auteur]
Université de Lille
Guerreschi, Pierre [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc]
Mortier, Laurent [Auteur]
Thérapies Lasers Assistées par l'Image pour l'Oncologie (ONCO-THAI) - U1189
Quesnel, Bruno [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172
Marchetti, Philippe [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172
Kluza, Jerome [Auteur]
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172
Trinh, Anne [Auteur]

Journal title :

Cell death & disease

Abbreviated title :

Cell Death Dis.

Volume number :

9

Pages :

325

Publication date :

2018-02-27

ISSN :

2041-4889

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [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 ...
Show more >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.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
CNRS
Inserm
Institut Pasteur de Lille
Université de Lille

Collections :

• Advanced Drug Delivery Systems (ADDS) - U1008
• IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483
• Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
• Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290
• Thérapies Lasers Assistées par l'Image pour l'Oncologie (ONCO-THAI) - U1189

Submission date :

2021-09-02T07:01:13Z
2021-11-17T07:27:33Z
2024-02-23T11:41:53Z
2024-02-23T11:51:33Z