title: Oxidative phosphorylation is impaired by prolonged hypoxia in breast and possibly in cervix carcinoma.
abstract: It has been assumed that oxidative phosphorylation (OxPhos) in solid tumors is severely reduced due to cytochrome c oxidase substrate restriction, although the measured extracellular oxygen concentration in hypoxic areas seems not limiting for this activity. To identify alternative hypoxia-induced OxPhos depressing mechanisms, an integral analysis of transcription, translation, enzyme activities and pathway fluxes was performed on glycolysis and OxPhos in HeLa and MCF-7 carcinomas. In both neoplasias exposed to hypoxia, an early transcriptional response was observed after 8h (two times increased glycolysis-related mRNA synthesis promoted by increased HIF-1alpha levels). However, major metabolic remodeling was observed only after 24h hypoxia: increased glycolytic protein content (1-5-times), enzyme activities (2-times) and fluxes (4-6-times). Interestingly, in MCF-7 cells, 24h hypoxia decreased OxPhos flux (4-6-fold), and 2-oxoglutarate dehydrogenase and glutaminase activities (3-fold), with no changes in respiratory complexes I and IV activities. In contrast, 24h hypoxia did not significantly affect HeLa OxPhos flux; neither mitochondria related mRNAs, protein contents or enzyme activities, although the enhanced glycolysis became the main ATP supplier. Thus, prolonged hypoxia (a) targeted some mitochondrial enzymes in MCF-7 but not in HeLa cells, and (b) induced a transition from mitochondrial towards a glycolytic-dependent energy metabolism in both MCF-7 and HeLa carcinomas.
authors.affiliation: Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, México DF, Mexico. saren960104@hotmail.com
authors.forename: Sara
authors.initials: S
authors.lastname: Rodríguez-Enríquez
authors.forename: Liliana
authors.initials: L
authors.lastname: Carreño-Fuentes
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Gallardo-Pérez
authors.forename: Emma
authors.initials: E
authors.lastname: Saavedra
authors.forename: Héctor
authors.initials: H
authors.lastname: Quezada
authors.forename: Alicia
authors.initials: A
authors.lastname: Vega
authors.forename: Alvaro
authors.initials: A
authors.lastname: Marín-Hernández
authors.forename: Viridiana
authors.initials: V
authors.lastname: Olín-Sandoval
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Torres-Márquez
authors.forename: Rafael
authors.initials: R
authors.lastname: Moreno-Sánchez
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D042967:Electron Transport Complex I / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006367:HeLa Cells; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D007655:Ketoglutarate Dehydrogenase Complex / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007655:Ketoglutarate Dehydrogenase Complex; D005972:Glutaminase; D042967:Electron Transport Complex I