title: Inactivation of the HIF-1α/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants.
abstract: Cancer cells can undergo a metabolic reprogramming from oxidative phosphorylation to glycolysis that allows them to adapt to nutrient-poor microenvironments, thereby imposing a selection for aggressive variants. However, the mechanisms underlying this reprogramming are not fully understood. Using complementary approaches in validated cell lines and freshly obtained human specimens, we report here that mitochondrial respiration and oxidative phosphorylation are slowed in metastatic melanomas, even under normoxic conditions due to the persistence of a high nuclear expression of hypoxia-inducible factor-1α (HIF-1α). Pharmacologic or genetic blockades of the HIF-1α pathway decreased glycolysis and promoted mitochondrial respiration via specific reduction in the expression of pyruvate dehydrogenase kinase-3 (PDK3). Inhibiting PDK3 activity by dichloroacetate (DCA) or siRNA-mediated attenuation was sufficient to increase pyruvate dehydrogenase activity, oxidative phosphorylation, and mitochondrial reactive oxygen species generation. Notably, DCA potentiated the antitumor effects of elesclomol, a pro-oxidative drug currently in clinical development, both by limiting cell proliferation and promoting cell death. Interestingly, this combination was also effective against BRAF V600E-mutant melanoma cells that were resistant to the BRAF inhibitor vemurafenib. Cotreatment of melanomas with DCA and elesclomol in vivo achieved a more durable response than single agent alone. Our findings offer a preclinical validation of the HIF-1/PDK3 bioenergetic pathway as a new target for therapeutic intervention in metastatic melanoma, opening the door to innovative combinations that might eradicate this disease.
authors.affiliation: Unit 837 Equipe 4 Inserm and Faculté de Médecine, Université de Lille II 1 Place, Verdun Cedex, CHRU Lille, France.
authors.forename: Jérome
authors.initials: J
authors.lastname: Kluza
authors.forename: Paola
authors.initials: P
authors.lastname: Corazao-Rozas
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Touil
authors.forename: Manel
authors.initials: M
authors.lastname: Jendoubi
authors.forename: Cyril
authors.initials: C
authors.lastname: Maire
authors.forename: Pierre
authors.initials: P
authors.lastname: Guerreschi
authors.forename: Aurélie
authors.initials: A
authors.lastname: Jonneaux
authors.forename: Caroline
authors.initials: C
authors.lastname: Ballot
authors.forename: Stéphane
authors.initials: S
authors.lastname: Balayssac
authors.forename: Samuel
authors.initials: S
authors.lastname: Valable
authors.forename: Aurélien
authors.initials: A
authors.lastname: Corroyer-Dulmont
authors.forename: Myriam
authors.initials: M
authors.lastname: Bernaudin
authors.forename: Myriam
authors.initials: M
authors.lastname: Malet-Martino
authors.forename: Elisabeth Martin
authors.initials: EM
authors.lastname: de Lassalle
authors.forename: Patrice
authors.initials: P
authors.lastname: Maboudou
authors.forename: Pierre
authors.initials: P
authors.lastname: Formstecher
authors.forename: Renata
authors.initials: R
authors.lastname: Polakowska
authors.forename: Laurent
authors.initials: L
authors.lastname: Mortier
authors.forename: Philippe
authors.initials: P
authors.lastname: Marchetti
mesh_terms: D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D006834:Hydrazines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000631431:PDK3 protein, human; C000631437:Pdk3 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; C512195:elesclomol; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases