title: Tumor hypoxia and metabolism -- towards novel anticancer approaches.
abstract: The transcription factor hypoxia-inducible factor-1 (HIF-1) facilitates the induction of enzymes necessary for regulation of biological processes required for cell survival and the acquisition of an aggressive and invasive phenotype, such as regulation of the intracellular pH (pHi), anaerobic glycolysis, angiogenesis, migration/invasion... In this presentation, we will highlight some of the HIF-1-induced gene products - carbonic anhydrases IX and XII (CAs) and monocarboxylate transporters (MCTs) - which regulate the pHi by controlling export of metabolically-generated acids (carbonic and lactic acids). We reported that targeting these pHi-regulated processes through inhibition of either HIF-1-induced CAIX/CAXII or HIF-1-induced MCT4, MCT1 or Basigin/EMMPRIN/CD147 chaperone of MCTs, severely restricts glycolysis-generated ATP levels and tumor growth. In addition, we demonstrated that the Myc/HIF-1-targeted glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyzing a key step producing the NADH cofactor, activates the Akt pathway, thereby upregulating expression of the anti-apoptotic Bcl-xL. As a consequence, high expression of GAPDH contributes to tumor aggressiveness, in particular in the context Myc-driven B lymphomas. We propose that membrane-bound carbonic anhydrases (CAIX, CAXII), monocarboxylate transporters/chaperon Basigin (Myc-induced MCT1 and HIF-induced-MCT4) and GAPDH that are associated with exacerbated tumor metabolism, represent new potential targets for anticancer therapy.
authors.affiliation: Unité 1065, équipe « contrôle métabolique des morts cellulaires », Institut national de la santé et de la recherche médicale, centre méditerranéen de médecine moléculaire (C3M), 06204 Nice, France. chiche@unice.fr
authors.forename: Johanna
authors.initials: J
authors.lastname: Chiche
authors.forename: Jean-Ehrland
authors.initials: JE
authors.lastname: Ricci
authors.forename: Jacques
authors.initials: J
authors.lastname: Pouysségur
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000627:therapeutic use*; D015507:Drugs, Investigational / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000502:physiology; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D051793:Hypoxia-Inducible Factor 1; D005947:Glucose