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dc.contributor.authorNavarro, Paloma
dc.contributor.authorBueno, Maria J
dc.contributor.authorZagorac, Ivana 
dc.contributor.authorMondejar, Tamara
dc.contributor.authorSanchez, Jesus
dc.contributor.authorMouron, Silvana Andrea 
dc.contributor.authorMuñoz Peralta, Javier 
dc.contributor.authorGómez-López, Gonzalo 
dc.contributor.authorJimenez-Renard, Veronica
dc.contributor.authorMulero Francisca, F 
dc.contributor.authorChandel, Navdeep S
dc.contributor.authorQuintela Fandino, Miguel Angel 
dc.date.accessioned2019-07-11T09:43:23Z
dc.date.available2019-07-11T09:43:23Z
dc.date.issued2016-06-21
dc.identifier.citationCell Rep. 2016;15(12):2705-18es_ES
dc.identifier.issn22111247es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/7891
dc.description.abstractEpithelial malignancies are effectively treated by antiangiogenics; however, acquired resistance is a major problem in cancer therapeutics. Epithelial tumors commonly have mutations in the MAPK/Pi3K-AKT pathways, which leads to high-rate aerobic glycolysis. Here, we show how multikinase inhibitor antiangiogenics (TKIs) induce hypoxia correction in spontaneous breast and lung tumor models. When this happens, the tumors downregulate glycolysis and switch to long-term reliance on mitochondrial respiration. A transcriptomic, metabolomic, and phosphoproteomic study revealed that this metabolic switch is mediated by downregulation of HIF1α and AKT and upregulation of AMPK, allowing uptake and degradation of fatty acids and ketone bodies. The switch renders mitochondrial respiration necessary for tumor survival. Agents like phenformin or ME344 induce synergistic tumor control when combined with TKIs, leading to metabolic synthetic lethality. Our study uncovers mechanistic insights in the process of tumor resistance to TKIs and may have clinical applicability.es_ES
dc.description.sponsorshipM.Q.-F. is a recipient of the following grants: FIS PI10/0288 and FIS PI13/00430 from the Ministry of Health (Spain), 2010-BECA-RETORNO from theAECC Scientific Foundation, and donations from the Rosae Foundation andAvon Espan ̃a S.A.U. I.Z. is a recipient of La Caixa-CNIO PhD 2011 fellowship.M.Q.-F. received research funds from Boehringer-Ingelheim and Novartis.es_ES
dc.language.isoenges_ES
dc.publisherCELL PRESSes_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAngiogenesis Inhibitors es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshCell Proliferation es_ES
dc.subject.meshCell Respiration es_ES
dc.subject.meshCellular Reprogramming es_ES
dc.subject.meshDisease Models, Animales_ES
dc.subject.meshDown-Regulation es_ES
dc.subject.meshDrug Resistance, Neoplasm es_ES
dc.subject.meshFatty Acids es_ES
dc.subject.meshFemale es_ES
dc.subject.meshGlucose es_ES
dc.subject.meshGlycolysis es_ES
dc.subject.meshHumans es_ES
dc.subject.meshKetone Bodies es_ES
dc.subject.meshMetabolome es_ES
dc.subject.meshMice, Inbred C57BL es_ES
dc.subject.meshMice, Nude es_ES
dc.subject.meshMitochondria es_ES
dc.subject.meshMitochondrial Degradationes_ES
dc.subject.meshNeoplasms es_ES
dc.subject.meshOxygen es_ES
dc.subject.meshPhenylurea Compounds es_ES
dc.subject.meshPhosphoproteins es_ES
dc.subject.meshProtein Kinase Inhibitors es_ES
dc.subject.meshPyridines es_ES
dc.subject.meshSignal Transduction es_ES
dc.titleTargeting Tumor Mitochondrial Metabolism Overcomes Resistance to Antiangiogenicses_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID27292634es_ES
dc.format.volume15es_ES
dc.format.number12es_ES
dc.format.page2705-18es_ES
dc.identifier.doi10.1016/j.celrep.2016.05.052es_ES
dc.contributor.funderMinisterio de Sanidad y Consumo (España)es_ES
dc.contributor.funderNovartis Farmaceutica S.A.es_ES
dc.contributor.funderFundación La Caixaes_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn2211-1247es_ES
dc.relation.publisherversionhttps://doi.org/10.1016/j.celrep.2016.05.052es_ES
dc.identifier.journalCell reportses_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Unidades técnicas::Unidad de Investigación Clínica de Cáncer de Mamaes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/FIS/PI10/0288es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/FIS/PI13/00430es_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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Atribución-NoComercial-CompartirIgual 4.0 Internacional
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