KSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levels

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dc.contributor.authorLlobet Navàs, David
dc.contributor.authorEritja Sánchez, Núria
dc.contributor.authorDomingo, Mónica
dc.contributor.authorBergadà Bertran, Laura
dc.contributor.authorMirantes Barbeito, Cristina
dc.contributor.authorSantacana Espasa, Maria
dc.contributor.authorPallares, Judit
dc.contributor.authorMacià Armengol, Anna
dc.contributor.authorYeramian Hakim, Andree
dc.contributor.authorEncinas Martín, Mario
dc.contributor.authorMoreno-Bueno, Gema
dc.contributor.authorPalacios, José
dc.contributor.authorLewis, Robert E.
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorDolcet Roca, Xavier
dc.date.accessioned2015-02-02T09:06:55Z
dc.date.available2015-02-02T09:06:55Z
dc.date.issued2011
dc.description.abstractThe Raf/MEK/extracellular signal-regulated kinase (ERK) pathway participates in many processes altered in development and progression of cancer in human beings such as proliferation, transformation, differentiation, and apoptosis. Kinase suppressor of Ras 1 (KSR1) can interact with various kinases of the Raf/ MEK/extracellular signal-regulated kinase pathway to enhance its activation. The role of KSR1 in endometrial carcinogenesis was investigated. cDNA and tissue microarrays demonstrated that expression of KSR1 was up-regulated in endometrial carcinoma. Furthermore, inhibition of KSR1 expression by specific small hairpin RNA resulted in reduction of both proliferation and anchorage-independent cell growth properties of endometrial cancer cells. Because inhibition of apoptosis has a pivotal role in endometrial carcinogenesis, the effects of KSR1 in regulation of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis were investigated. KSR1 knock-down sensitized resistant endometrial cell lines to both TRAIL- and Fas-induced apoptosis. Sensitization to TRAIL and agonistic anti-Fas antibody was caused by down-regulation of FLIP (FLICE-inhibitory protein). Also investigated was the molecular mechanism by which KSR1 regulates FLIP protein levels. It was demonstrated that KSR1 small hairpin RNA did not affect FLIP transcription or degradation. Rather, FLIP down-regulation was caused by Fas-associated death domain protein–dependent inhibition of FLIP translation triggered after TRAIL stimulation in KSR1-silenced cells. Re-expression of heterologous KSR1 in cells with down-regulated endogenous KSR1 restored FLIP protein levels and TRAIL resistance. In conclusion, KSR1 regulates endometrial sensitivity to TRAIL by regulating FLIP levels.ca_ES
dc.identifier.doihttps://doi.org/10.1016/j.ajpath.2010.12.041
dc.identifier.idgrec016651
dc.identifier.urihttp://hdl.handle.net/10459.1/47778
dc.language.isoengca_ES
dc.publisherElsevier Incca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1016/j.ajpath.2010.12.041ca_ES
dc.relation.ispartofAmerican Journal of Pathology, 2011, vol. 178, núm. 4, p. 1529-1543ca_ES
dc.rights(c) American Society for Investigative Pathology, 2011
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/*
dc.subject.otherEndometri -- Càncerca_ES
dc.titleKSR1 is overexpressed in endometrial carcinoma and regulates proliferation and TRAIL-induced apoptosis by modulating FLIP levelsca_ES
dc.typearticleca_ES
dc.type.versionpublishedVersionca_ES
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