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Carcinogenesis Advance Access originally published online on December 16, 2005
Carcinogenesis 2006 27(5):925-935; doi:10.1093/carcin/bgi315
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase

Gema Santamaría 1, {dagger}, Marta Martínez-Diez 1, {dagger}, Isabel Fabregat 2 and José M. Cuezva 1, *

1 Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, 28049 Madrid, Spain and 2 IDIBELL-Institut de Recerca Oncològica, 08907 L'Hospitalet, Barcelona, Spain

* To whom correspondence should be addressed at: Centro de Biología Molecular ‘Severo Ochoa’, Universidad Autónoma de Madrid, 28049 Madrid, Spain. Tel: 34 91 497 4866; Fax: 34 91 497 4799; Email: jmcuezva{at}cbm.uam.es

There is a large body of clinical data documenting that most human carcinomas contain reduced levels of the catalytic subunit of the mitochondrial H+-ATP synthase. In colon and lung cancer this alteration correlates with a poor patient prognosis. Furthermore, recent findings in colon cancer cells indicate that downregulation of the H+-ATP synthase is linked to the resistance of the cells to chemotherapy. However, the mechanism by which the H+-ATP synthase participates in cancer progression is unknown. In this work, we show that inhibitors of the H+-ATP synthase delay staurosporine (STS)-induced cell death in liver cells that are dependent on oxidative phosphorylation for energy provision whereas it has no effect on glycolytic cells. Efficient execution of cell death requires the generation of reactive oxygen species (ROS) controlled by the activity of the H+-ATP synthase in a process that is concurrent with the rapid disorganization of the cellular mitochondrial network. The generation of ROS after STS treatment is highly dependent on the mitochondrial membrane potential and most likely caused by reverse electron flow to Complex I. The generated ROS promote the carbonylation and covalent modification of cellular and mitochondrial proteins. Inhibition of the activity of the H+-ATP synthase blunted ROS production prevented the oxidation of cellular proteins and the modification of mitochondrial proteins delaying the release of cytochrome c and the execution of cell death. The results in this work establish the downregulation of the H+-ATP synthase, and thus of oxidative phosphorylation, as part of the molecular strategy adapted by cancer cells to avoid ROS-mediated cell death. Furthermore, the results provide a mechanistic explanation to understand chemotherapeutic resistance of cancer cells that rely on glycolysis as the main energy provision pathway.


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