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

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Carcinogenesis following peer review. The definitive publisher-authenticated version Carcinogenesis 2006 27(5):925-935 is available at: http://dx.doi.org/10.1093/carcin/bgi315

Detalles Bibliográficos
Autores: Santamaría, Gema, Martínez-Díez, Marta, Fabregat, Isabel, Cuezva, José M.
Tipo de recurso: artículo
Fecha de publicación:2005
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/4825
Acceso en línea:http://hdl.handle.net/10261/4825
Access Level:acceso abierto
Palabra clave:H+-ATP synthase
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spelling Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthaseSantamaría, GemaMartínez-Díez, MartaFabregat, IsabelCuezva, José M.H+-ATP synthaseThis is a pre-copy-editing, author-produced PDF of an article accepted for publication in Carcinogenesis following peer review. The definitive publisher-authenticated version Carcinogenesis 2006 27(5):925-935 is available at: http://dx.doi.org/10.1093/carcin/bgi315There 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.G.S. and M.M-D. were supported by pre-doctoral fellowships from the Ministerio de Ciencia y Tecnología. This work was supported by grants from the Ministerio de Sanidad y Consumo (PI041255), Comunidad de Madrid (SAL/0026/2004) and Ministerio de Ciencia y Tecnología (BMC2001-0710). The CBMSO receives an institutional grant from Fundación Ramón Areces.Peer reviewedOxford University PressMinisterio de Ciencia y Tecnología (España)Ministerio de Sanidad y Consumo (España)Fundación Ramón Areces200820082005info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501982664 bytesapplication/pdfhttp://hdl.handle.net/10261/4825reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglésinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/48252026-05-22T06:33:51Z
dc.title.none.fl_str_mv Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase
title Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase
spellingShingle Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase
Santamaría, Gema
H+-ATP synthase
title_short Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase
title_full Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase
title_fullStr Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase
title_full_unstemmed Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase
title_sort Efficient execution of cell death in non-glycolytic cells requires the generation of ROS controlled by the activity of mitochondrial H+-ATP synthase
dc.creator.none.fl_str_mv Santamaría, Gema
Martínez-Díez, Marta
Fabregat, Isabel
Cuezva, José M.
author Santamaría, Gema
author_facet Santamaría, Gema
Martínez-Díez, Marta
Fabregat, Isabel
Cuezva, José M.
author_role author
author2 Martínez-Díez, Marta
Fabregat, Isabel
Cuezva, José M.
author2_role author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia y Tecnología (España)
Ministerio de Sanidad y Consumo (España)
Fundación Ramón Areces
dc.subject.none.fl_str_mv H+-ATP synthase
topic H+-ATP synthase
description This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Carcinogenesis following peer review. The definitive publisher-authenticated version Carcinogenesis 2006 27(5):925-935 is available at: http://dx.doi.org/10.1093/carcin/bgi315
publishDate 2005
dc.date.none.fl_str_mv 2005
2008
2008
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
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dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/4825
url http://hdl.handle.net/10261/4825
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 982664 bytes
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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