Hernandez-Resendiz 2018 J Cell Physiol

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Hernández-Reséndiz I, Gallardo-Pérez JC, López-Macay A, Robledo-Cadena DX, García-Villa E, Gariglio P, Saavedra E, Moreno-Sánchez R, Rodríguez-Enríquez S (2018) Mutant p53R248Q downregulates oxidative phosphorylation and upregulates glycolysis under normoxia and hypoxia in human cervix cancer cells. J Cell Physiol 234:5524-36.

» PMID: 30272821 Open Access

Hernandez-Resendiz I, Gallardo-Perez JC, Lopez-Macay A, Robledo-Cadena DX, Garcia-Villa E, Gariglio P, Saavedra E, Moreno-Sanchez R, Rodriguez-Enriquez S (2018) J Cell Physiol

Abstract: Mutations in p53 are strongly associated with several highly malignant cancer phenotypes but its role in regulating energy metabolism has not been completely elucidated. The effect on glycolysis and oxidative phosphorylation (OxPhos) of mutant p53R248Q overexpression in HeLa cells (HeLa-M) was analyzed and compared with cells overexpressing wild-type p53 (HeLa-H) and nontransfected cells containing negligible p53 levels (HeLa-L). p53R248Q overexpression induced early cell detachment during in vitro growth; however, detached HeLa-M cells showed high viability, shorter generation time and significant diminution in the adhesion proteins E-cadherin and β-catenin versus HeLa-H and HeLa-L cells. Under normoxia, a lower growth rate of attached HeLa-M cells correlated with decreased levels of proliferating cell nuclear antigen (PCNA), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), adenosine monophosphate-activated protein kinase (AMPK), mitochondrial proteins (20-80%) and OxPhos flux (69 ± 12%). On the contrary, HeLa-M also showed increased contents of CDKN1A, nuclear factor κB (NF-κB), c-MYC, hypoxia-inducible factor 1-α (HIF-1α; 1-4 times), glycolytic HIF-1α targets (2-4 times), and glycolysis flux (2-fold) versus HeLa-H. In consequence, glycolysis provided ~70% of the cellular adenosine triphosphate (ATP) in HeLa-M cells under normoxia whereas, OxPhos predominated (65-82%) in HeLa-H and HeLa-L cells. Pifithrin-α, a specific p53 inhibitor, did not alter the p53R248Q target protein contents and OxPhos and glycolytic fluxes, and a poor HIF-1α-p53R248Q interaction was attained, in HeLa-M cells. These observations suggested that p53R248Q deficiently interacted with pifithrin-α and HIF-1α. Therefore, lower mitochondrial biogenesis, deficient HIF-1α/mutant p53 interaction, and development of a pseudohypoxic state under normoxia were the apparent biochemical mechanisms underlying glycolysis activation and OxPhos downregulation in HeLa-M cells.

Keywords: Cancer cells, Glycolysis, Mutant p53, Oxidative phosphorylation Bioblast editor: Plangger M O2k-Network Lab: MX Mexiko City Moreno-Sanchez R

Labels: MiParea: Respiration, Genetic knockout;overexpression  Pathology: Cancer 

Organism: Human  Tissue;cell: HeLa  Preparation: Intact cells 

Coupling state: LEAK 

HRR: Oxygraph-2k 

Labels, 2018-10