Energy metabolism transition in multi-cellular human tumor spheroids
Por:
Rodríguez-Enríquez S., Gallardo-Pérez J.C., Avilés-Salas A., Marín-Hernández A., Carreño-Fuentes L., Maldonado-Lagunas V., Moreno-Sánchez R.
Publicada:
1 ene 2008
Resumen:
It is thought that glycolysis is the predominant energy pathway in cancer, particularly in solid and poorly vascularized tumors where hypoxic regions develop. To evaluate whether glycolysis does effectively predominate for ATP supply and to identify the underlying biochemical mechanisms, the glycolytic and oxidative phosphorylation (OxPhos) fluxes, ATP/ADP ratio, phosphorylation potential, and expression and activity of relevant energy metabolism enzymes were determined in multi-cellular tumor spheroids, as a model of human solid tumors. In HeLa and Hek293 young-spheroids, the OxPhos flux and cytochrome c oxidase protein content and activity were similar to those observed in monolayer cultured cells, whereas the glycolytic flux increased two- to fourfold; the contribution of OxPhos to ATP supply was 60%. In contrast, in old-spheroids, OxPhos, ATP content, ATP/ADP ratio, and phosphorylation potential diminished 50-70%, as well as the activity (88%) and content (3 times) of cytochrome c oxidase. Glycolysis and hexokinase increased significantly (both, 4 times); consequently glycolysis was the predominant pathway for ATP supply (80%). These changes were associated with an increase (3.3 times) in the HIF-1a content. After chronic exposure, both oxidative and glycolytic inhibitors blocked spheroid growth, although the glycolytic inhibitors, 2-deoxyglucose and gossypol (IC50 of 15-17 nM), were more potent than the mitochondrial inhibitors, casiopeina II-gly, laherradurin, and rhodamine 123 (IC50 > 100 nM). These results suggest that glycolysis and OxPhos might be considered as metabolic targets to diminish cellular proliferation in poorly vascularized, hypoxic solid tumors. © 2008 Wiley-Liss, Inc.
Filiaciones:
Rodríguez-Enríquez S.:
Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico, Mexico
Departamento de Bioquimica, Instituto Nacional de Cardiologia, Juan Badiano No. 1, Tlalpan, Mexico D F 14080, Mexico
Gallardo-Pérez J.C.:
Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico, Mexico
Avilés-Salas A.:
Departamentos de Biología Molecular Y de Paralogía, Instituto Nacional de Cancerología, Mexico, Mexico
Marín-Hernández A.:
Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico, Mexico
Carreño-Fuentes L.:
Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico, Mexico
Maldonado-Lagunas V.:
Departamentos de Biología Molecular Y de Paralogía, Instituto Nacional de Cancerología, Mexico, Mexico
Moreno-Sánchez R.:
Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico, Mexico
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