Oncotarget

Research Papers:

Down-regulation of oxidative phosphorylation in the liver by expression of the ATPase inhibitory factor 1 induces a tumor-promoter metabolic state

Fulvio Santacatterina _, Laura Sánchez-Cenizo, Laura Formentini, Maysa A. Mobasher, Estela Casas, Carlos B. Rueda, Inmaculada Martínez-Reyes, Cristina Núñez de Arenas, Javier García-Bermúdez, Juan M. Zapata, María Sánchez-Aragó, Jorgina Satrústegui, Ángela M. Valverde and José M. Cuezva

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:490-508. https://doi.org/10.18632/oncotarget.6357

Metrics: PDF 3446 views  |   HTML 4148 views  |   ?  


Abstract

Fulvio Santacatterina1,2,3,*, Laura Sánchez-Cenizo1,2,3,*, Laura Formentini1,2,3,*, Maysa A. Mobasher4,5, Estela Casas1,2,3, Carlos B. Rueda1,2,6, Inmaculada Martínez-Reyes1,2,3, Cristina Núñez de Arenas1,2, Javier García-Bermúdez1,2,3, Juan M. Zapata4, María Sánchez-Aragó1,2,3, Jorgina Satrústegui1,2,6, Ángela M. Valverde4,5 and José M. Cuezva1,2,3

1 Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain

2 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

3 Centro de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain

4 Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain

5 Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain

6 Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain

* These authors have equally contributed to this work

Correspondence to:

José M. Cuezva, email:

Keywords: ATPase inhibitory factor 1, cancer, energy metabolism, mitochondria, reactive oxygen species

Received: June 30, 2015 Accepted: November 14, 2015 Published: November 22, 2015

Abstract

The ATPase Inhibitory Factor 1 (IF1) is an inhibitor of the mitochondrial H+-ATP synthase that regulates the activity of both oxidative phosphorylation (OXPHOS) and cell death. Here, we have developed transgenic Tet-On and Tet-Off mice that express a mutant active form of hIF1 in the hepatocytes to restrain OXPHOS in the liver to investigate the relevance of mitochondrial activity in hepatocarcinogenesis. The expression of hIF1 promotes the inhibition of OXPHOS in both Tet-On and Tet-Off mouse models and induces a state of metabolic preconditioning guided by the activation of the stress kinases AMPK and p38 MAPK. Expression of the transgene significantly augmented proliferation and apoptotic resistance of carcinoma cells, which contributed to an enhanced diethylnitrosamine-induced liver carcinogenesis. Moreover, the expression of hIF1 also diminished acetaminophen-induced apoptosis, which is unrelated to differences in permeability transition pore opening. Mechanistically, cell survival in hIF1-preconditioned hepatocytes results from a nuclear factor-erythroid 2-related factor (Nrf2)-guided antioxidant response. The results emphasize in vivo that a metabolic phenotype with a restrained OXPHOS in the liver is prone to the development of cancer.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 6357