S6K1 deficiency protects against apoptosis in hepatocytes

PMCID: PMC2752632

Detalles Bibliográficos
Autores: González-Rodríguez, Águeda, Alba, Javier, Zimmerman, Valeri, Kozma, Sara C., Valverde, Ángela M.
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2009
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/13194
Acceso en línea:http://hdl.handle.net/10261/13194
Access Level:acceso abierto
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spelling S6K1 deficiency protects against apoptosis in hepatocytesGonzález-Rodríguez, ÁguedaAlba, JavierZimmerman, ValeriKozma, Sara C.Valverde, Ángela M.PMCID: PMC2752632The mammalian target of rapamycin (mTOR)/S6K1 signaling pathway controls cell growth and proliferation. To assess the importance of S6K1 in the balance between death and survival in the liver, we have generated immortalized hepatocyte cell lines from wild-type and S6K1-deficient (S6K1(-/-)) mice. In S6K1(-/-) hepatocytes, caspase-8 and the pro-apoptotic protein Bid were constitutively down-regulated as compared with wild-type. Moreover, S6K1(-/-) hepatocytes failed to respond to the apoptotic trigger of death receptor activation. Neither caspase-8 activation nor FLIP(L) degradation in response to tumor necrosis factor alpha (TNF-α) or anti-Fas antibody (Jo2) was observed in cells lacking S6K1. Downstream events such as Bid cleavage, cytochrome C release, caspase-3 activation, DNA laddering, as well as the percentage of apoptotic cells were attenuated as compared with wild-type. In addition, the anti-apoptotic protein Bclx(L) was down-regulated in TNF-α-treated or Jo2-treated wild-type hepatocytes, but this response was abolished in S6K1(-/-) cells. In vivo, S6K1-deficient mice were protected against concanavalin A-induced apoptosis. The withdrawal of growth factors strongly induced apoptosis in wild-type, but not in S6K1(-/-) hepatocytes. S6K1 deficiency did not decrease Bclx(L)/Bim ratio on serum withdrawal, thereby protecting cells from cytochrome C release and DNA fragmentation. At the molecular level, the lack of S6K1-mediated negative feedback decreased insulin receptor substrate-1 (IRS-1) serine phosphorylation, resulting in activation of survival pathways mediated by phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase (ERK). However, S6K1(-/-) hepatocytes underwent apoptosis on serum withdrawal in combination with phosphatidylinositol 3-kinase (PI3K) or ERK inhibitors.[Conclusion] This finding might explain the mechanism of resistance to mTOR inhibitors in cancer treatments and strongly suggests that the inhibition of S6K1 could protect against acute liver failure and, in combination with inhibitors that abrogate the sustained activation of Akt and ERK, could improve the efficacy of hepatocarcinoma (HCC) treatment.Supported by grants BFU 2008-02420 and CIT-090100-2007-35 (MEC, Spain) and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto Carlos III, MSC, (Spain). S.C.K. and V.Z. are supported by NIH grants CA120475 and DK073802.Peer reviewedAmerican Association for the Study of Liver DiseasesJohn Wiley & SonsInstituto de Salud Carlos IIINational Institutes of Health (US)Ministerio de Educación y Ciencia (España)200920092009info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersion918459 bytesapplication/pdfhttp://hdl.handle.net/10261/13194reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1002/hep.22915info:eu-repo/semantics/openAccessoai:digital.csic.es:10261/131942026-05-22T06:33:51Z
dc.title.none.fl_str_mv S6K1 deficiency protects against apoptosis in hepatocytes
title S6K1 deficiency protects against apoptosis in hepatocytes
spellingShingle S6K1 deficiency protects against apoptosis in hepatocytes
González-Rodríguez, Águeda
title_short S6K1 deficiency protects against apoptosis in hepatocytes
title_full S6K1 deficiency protects against apoptosis in hepatocytes
title_fullStr S6K1 deficiency protects against apoptosis in hepatocytes
title_full_unstemmed S6K1 deficiency protects against apoptosis in hepatocytes
title_sort S6K1 deficiency protects against apoptosis in hepatocytes
dc.creator.none.fl_str_mv González-Rodríguez, Águeda
Alba, Javier
Zimmerman, Valeri
Kozma, Sara C.
Valverde, Ángela M.
author González-Rodríguez, Águeda
author_facet González-Rodríguez, Águeda
Alba, Javier
Zimmerman, Valeri
Kozma, Sara C.
Valverde, Ángela M.
author_role author
author2 Alba, Javier
Zimmerman, Valeri
Kozma, Sara C.
Valverde, Ángela M.
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
National Institutes of Health (US)
Ministerio de Educación y Ciencia (España)
description PMCID: PMC2752632
publishDate 2009
dc.date.none.fl_str_mv 2009
2009
2009
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/13194
url http://hdl.handle.net/10261/13194
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1002/hep.22915
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 918459 bytes
application/pdf
dc.publisher.none.fl_str_mv American Association for the Study of Liver Diseases
John Wiley & Sons
publisher.none.fl_str_mv American Association for the Study of Liver Diseases
John Wiley & Sons
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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