Oxidative phosphorylation is impaired by prolonged hypoxia in breast and possibly in cervix carcinoma.
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.
Rodríguez-Enríquez
Sara
S
Departamento de Bioquímica, Instituto Nacional de Cardiología Ignacio Chávez, México DF, Mexico. saren960104@hotmail.com
Carreño-Fuentes
Liliana
L
Gallardo-Pérez
Juan Carlos
JC
Saavedra
Emma
E
Quezada
Héctor
H
Vega
Alicia
A
Marín-Hernández
Alvaro
A
Olín-Sandoval
Viridiana
V
Torres-Márquez
M Eugenia
ME
Moreno-Sánchez
Rafael
R
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
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007655:Ketoglutarate Dehydrogenase Complex; D005972:Glutaminase; D042967:Electron Transport Complex I