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Biochim Biophys Acta. 2015 Dec;1853(12):3266-78. doi: 10.1016/j.bbamcr.2015.09.033. Epub 2015 Oct 3.

Dual regulation of energy metabolism by p53 in human cervix and breast cancer cells.

Author information

1
Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico.
2
Laboratorio de Biología y Genética Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional- Zacatenco, Mexico.
3
Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación, Mexico.
4
Departamento de Bioquímica, Instituto Nacional de Cardiología, Mexico. Electronic address: saren960201@hotmail.com.

Abstract

The role of p53 as modulator of OxPhos and glycolysis was analyzed in HeLa-L (cells containing negligible p53 protein levels) and HeLa-H (p53-overexpressing) human cervix cancer cells under normoxia and hypoxia. In normoxia, functional p53, mitochondrial enzyme contents, mitochondrial electrical potential (ΔΨm) and OxPhos flux increased in HeLa-H vs. HeLa-L cells; whereas their glycolytic enzyme contents and glycolysis flux were unchanged. OxPhos provided more than 70% of the cellular ATP and proliferation was abolished by anti-mitochondrial drugs in HeLa-H cells. In hypoxia, both cell proliferations were suppressed, but HeLa-H cells exhibited a significant decrease in OxPhos protein contents, ΔΨm and OxPhos flux. Although glycolytic function was also diminished vs. HeLa-L cells in hypoxia, glycolysis provided more than 60% of cellular ATP in HeLa-H cells. The energy metabolism phenotype of HeLa-H cells was reverted to that of HeLa-L cells by incubating with pifithrin-α, a p53-inhibitor. In normoxia, the energy metabolism phenotype of breast cancer MCF-7 cells was similar to that of HeLa-H cells, whereas p53shRNAMCF-7 cells resembled the HeLa-L cell phenotype. In hypoxia, autophagy proteins and lysosomes contents increased 2-5 times in HeLa-H cells suggesting mitophagy activation. These results indicated that under normoxia p53 up-regulated OxPhos without affecting glycolysis, whereas under hypoxia, p53 down-regulated both OxPhos (severely) and glycolysis (weakly). These p53 effects appeared mediated by the formation of p53-HIF-1α complexes. Therefore, p53 exerts a dual and contrasting regulatory role on cancer energy metabolism, depending on the O₂level.

KEYWORDS:

Glycolysis; Hypoxia; Oxidative phosphorylation; Tumor cells; p53

PMID:
26434996
DOI:
10.1016/j.bbamcr.2015.09.033
[Indexed for MEDLINE]
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