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dc.contributor.authorLozano Sánchez, Jesús 
dc.contributor.authorCorominas-Faja, Bruna
dc.contributor.authorCuyàs, Elisabet
dc.contributor.authorCufí, Sílvia
dc.contributor.authorVerdura, Sara
dc.contributor.authorFernández-Arroyo, Salvador
dc.contributor.authorBorras Linares, María Isabel 
dc.contributor.authorMartin-Castillo, Begoña
dc.contributor.authorMartin, Ángel G.
dc.contributor.authorLupu, Ruth
dc.contributor.authorNonell-Canals, Alfons
dc.contributor.authorSanchez-Martinez, Melchor
dc.contributor.authorMicol Molina, Vicente
dc.contributor.authorJoven, Jorge
dc.contributor.authorSegura Carretero, Antonio 
dc.contributor.authorMenendez, Javier A.
dc.date.accessioned2018-06-04T07:47:01Z
dc.date.available2018-06-04T07:47:01Z
dc.date.issued2018-02-14
dc.identifier.citationCorominas-Faja, Bruna; et. al. Extra-virgin olive oil contains a metabolo-epigenetic inhibitor of cancer stem cells. Carcinogenesis, 2018, Vol. 39, No. 4, 601–613 [http://hdl.handle.net/10481/51214]es_ES
dc.identifier.urihttp://hdl.handle.net/10481/51214
dc.descriptionWe are grateful to Custodio Borrego for giving us free use of the photograph he took of EVOO and olive trees in Granada (Spain), which have been included in Figure 7. This work has been awarded with the IV Premio Internacional Castillo de Canena de Investigación Oleícola ‘LUIS VAÑÓ’(IV Edition of Castillo de Canena LUIS VAÑÓ Award for Research on Olive Cultivation and Olive Oil; UC Davis Olive Center, Castillo de Canena, and Universidad de Jaén).es_ES
dc.descriptionThe authors would like to thank Dr Kenneth McCreath for editorial support. We are greatly indebted to Prof Robert A. Weinberg (Whitehead Institute for Biomedical Research, Cambridge, MA) for providing the HMLERshCntrol/HMLERshEcad cells used in this work.es_ES
dc.description.abstractTargeting tumor-initiating, drug-resistant populations of cancer stem cells (CSC) with phytochemicals is a novel paradigm for cancer prevention and treatment. We herein employed a phenotypic drug discovery approach coupled to mechanism-of-action profiling and target deconvolution to identify phenolic components of extra virgin olive oil (EVOO) capable of suppressing the functional traits of CSC in breast cancer (BC). In vitro screening revealed that the secoiridoid decarboxymethyl oleuropein aglycone (DOA) could selectively target subpopulations of epithelial-like, aldehyde dehydrogenase (ALDH)-positive and mesenchymal-like, CD44+CD24−/low CSC. DOA could potently block the formation of multicellular tumorspheres generated from single-founder stem-like cells in a panel of genetically diverse BC models. Pretreatment of BC populations with noncytotoxic doses of DOA dramatically reduced subsequent tumor-forming capacity in vivo. Mice orthotopically injected with CSC-enriched BC-cell populations pretreated with DOA remained tumor-free for several months. Phenotype microarray-based screening pointed to a synergistic interaction of DOA with the mTOR inhibitor rapamycin and the DNA methyltransferase (DNMT) inhibitor 5-azacytidine. In silico computational studies indicated that DOA binds and inhibits the ATP-binding kinase domain site of mTOR and the S-adenosyl-l-methionine (SAM) cofactorbinding pocket of DNMTs. FRET-based Z-LYTE™ and AlphaScreen-based in vitro assays confirmed the ability of DOA to function as an ATP-competitive mTOR inhibitor and to block the SAM-dependent methylation activity of DNMTs. Our systematic in vitro, in vivo and in silico approaches establish the phenol-conjugated oleoside DOA as a dual mTOR/DNMT inhibitor naturally occurring in EVOO that functionally suppresses CSC-like states responsible for maintaining tumorinitiating cell properties within BC populations.es_ES
dc.description.sponsorshipThis work was supported by grants from the Ministerio de Ciencia e Innovación (Grant SAF2016-80639-P to J.A.M.), Plan Nacional de I+D+I, Spain, the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR; Grant 2014 SGR229 to J.A.M.), Departament d’Economia i Coneixement, Catalonia, Spain, the Andalusian Regional Government Council of Innovation and Science (Grant P11-CTS-7625 to A.S.-C.), the Ministerio de Economía, Industria y Competitividad, Spain (Grants AGL2015- 67995-C2-3-R and AGL2015-67995-C3-1-R to A.S.-C. and V.M.) and Conselleria d’Educació, Investigació, Cultura I Esport, Generalitat Valenciana, Spain (Grant PROMETEO/2016/006 to V.M). E.C. is supported by the Sara Borrell post doctoral contract (CD15/00033) from the Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria (FIS), Spain.es_ES
dc.language.isoenges_ES
dc.publisherOxford University Presses_ES
dc.rightsAtribución-NoComercial 3.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by-nc/3.0/es/*
dc.titleExtra-virgin olive oil contains a metabolo-epigenetic inhibitor of cancer stem cellses_ES
dc.typeinfo:eu-repo/semantics/articlees_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES
dc.identifier.doi10.1093/carcin/bgy023


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