title: Metabolic rewiring in cancer cells overexpressing the glucocorticoid-induced leucine zipper protein (GILZ): Activation of mitochondrial oxidative phosphorylation and sensitization to oxidative cell death induced by mitochondrial targeted drugs.
abstract: Cancer cell metabolism is largely controlled by oncogenic signals and nutrient availability. Here, we highlighted that the glucocorticoid-induced leucine zipper (GILZ), an intracellular protein influencing many signaling pathways, reprograms cancer cell metabolism to promote proliferation. We provided evidence that GILZ overexpression induced a significant increase of mitochondrial oxidative phosphorylation as evidenced by the augmentation in basal respiration, ATP-linked respiration as well as respiratory capacity. Pharmacological inhibition of glucose, glutamine and fatty acid oxidation reduced the activation of GILZ-induced mitochondrial oxidative phosphorylation. At glycolysis level, GILZ-overexpressing cells enhanced the expression of glucose transporters in their plasmatic membrane and showed higher glycolytic reserve.1H NMR metabolites quantification showed an up-regulation of amino acid biosynthesis. The GILZ-induced metabolic reprograming is present in various cancer cell lines regardless of their driver mutations status and is associated with higher proliferation rates persisting under metabolic stress conditions. Interestingly, high levels of OXPHOS made GILZ-overexpressing cells vulnerable to cell death induced by mitochondrial pro-oxidants. Altogether, these data indicate that GILZ reprograms cancer metabolism towards mitochondrial OXPHOS and sensitizes cancer cells to mitochondria-targeted drugs with pro-oxidant activities.
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172, JPArc, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: André
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172, JPArc, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Trinh
authors.affiliation: Laboratoire SPCMIB, UMR CNRS 5068 Université Paul Sabatier, 118 route de Narbonne, 31062, Toulouse Cedex 9, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Balayssac
authors.affiliation: CHU Lille, Centre de Biologie-Pathologie, Biologie et Thérapie cellulaire & Banque de Tissus, F-59000, Lille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Maboudou
authors.affiliation: CHU Lille, Centre de Biologie-Pathologie, Biologie et Thérapie cellulaire & Banque de Tissus, F-59000, Lille, France.
authors.forename: Salim
authors.initials: S
authors.lastname: Dekiouk
authors.affiliation: Laboratoire SPCMIB, UMR CNRS 5068 Université Paul Sabatier, 118 route de Narbonne, 31062, Toulouse Cedex 9, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Malet-Martino
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172, JPArc, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172, JPArc, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Idziorek
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172, JPArc, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Kluza
authors.affiliation: Univ. Lille, Inserm, CHU Lille, UMR-S 1172, JPArc, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, F-59000, Lille, France; CHU Lille, Centre de Biologie-Pathologie, Biologie et Thérapie cellulaire & Banque de Tissus, F-59000, Lille, France. Electronic address: philippe.marchetti@inserm.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D016503:Drug Delivery Systems; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D055442:Metabolome / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction; D013440:Sulfides / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D006834:Hydrazines; C103593:Luzp1 protein, mouse; D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; C512195:elesclomol
keywords: Cancer cell metabolism; Glucocorticoids; Mitochondria; ROS; TSC-22