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dc.contributor.authorMontero, Juan Carlos-
dc.contributor.authorChen, Xi-
dc.contributor.authorOcaña, Alberto-
dc.contributor.authorPandiella, Atanasio-
dc.date.accessioned2012-12-12T11:33:16Z-
dc.date.available2012-12-12T11:33:16Z-
dc.date.issued2012-
dc.identifierdoi: 10.1158/1535-7163.MCT-11-0723-
dc.identifierissn: 1535-7163-
dc.identifiere-issn: 1538-8514-
dc.identifier.citationMolecular Cancer Therapeutics 11(6): 1342-1352 (2012)-
dc.identifier.urihttp://hdl.handle.net/10261/62635-
dc.description.abstractmTOR is a serine/threonine kinase that acts by binding different sets of proteins forming two complexes, termed mTORC1 and mTORC2. mTOR is deregulated in a substantial proportion of ovarian tumors. Despite the use of drugs directed to mTOR in ongoing clinical trials, the functional relevance of the individual mTORC branches in ovarian cancer is not known. Here, we show that mTORC1 and mTORC2 were constitutively active in ovarian cancer cell lines. Knockdown of raptor or rictor, proteins required for the function of mTORC1 or mTORC2, respectively, resulted in profound inhibition of ovarian cancer cell proliferation. The knockdown of raptor had a more important inhibitory effect than the knockdown of rictor, indicating mTORC1 had a predominant role over mTORC2 in the control of ovarian cancer cell proliferation. Rapamycin decreased the proliferation of ovarian cancer cells, and this was accompanied by inhibition of the phosphorylation of S6, a protein used as readout of mTORC1 function. However, rapamycin had only amarginal effect on the phosphorylation status of 4E-BP1, anothermTORC1 substrate. Therefore, mTORC1 probably controls p4E-BP1 along two distinct pathways, one of them sensitive to rapamycin and another insensitive. The dual PI3K/mTOR inhibitor BEZ235 was more efficient than rapamycin in its inhibitory action on ovarian cancer cell proliferation. Biochemically, BEZ235 completely inhibited pS6, p4E-BP1, and pAkt. Our results suggest that broad-spectrum mTOR inhibitors that block mTORC1 and mTORC2 are more desirable for their clinical development in ovarian cancer than agents exclusively targeting one of the mTOR branches. ©2012 AACR.-
dc.description.sponsorshipThis work was supported by grants from the Ministry of Science and Innovation of Spain (BFU2009-07728/BMC; A. Pandiella) and by the Consejería de Sanidad de la Junta de Castilla y León (SAN196/SA03/ 07; J.C. Montero). X. Chen is supported by the Cancer Center Network Program from the Instituto de Salud Carlos III (RD06/0020/0041). Our Cancer Research Institute and the work carried out at our laboratory received support from the European Community through the Regional Development Funding Program(FEDER) and from the Fundación Ramón Areces.-
dc.language.isoeng-
dc.publisherAmerican Association for Cancer Research-
dc.rightsclosedAccess-
dc.titlePredominance of mTORC1 over mTORC2 in the regulation of proliferation of ovarian cancer cells: Therapeutic implications-
dc.typeartículo-
dc.identifier.doi10.1158/1535-7163.MCT-11-0723-
dc.date.updated2012-12-12T11:33:16Z-
dc.description.versionPeer Reviewed-
dc.contributor.funderJunta de Castilla y León-
dc.contributor.funderMinisterio de Ciencia e Innovación (España)-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderFundación Ramón Areces-
dc.contributor.funderEuropean Commission-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004837es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100004587es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/100008054es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100014180es_ES
dc.type.coarhttp://purl.org/coar/resource_type/c_6501es_ES
item.openairetypeartículo-
item.cerifentitytypePublications-
item.languageiso639-1en-
item.grantfulltextnone-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.fulltextNo Fulltext-
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