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dc.contributor.authorMachado, Susana
dc.contributor.authorSilva, Andreia
dc.contributor.authorDe Sousa-Coelho, Ana Luísa
dc.contributor.authorDuarte, Isabel
dc.contributor.authorGrenho, Ines
dc.contributor.authorSantos, Bruno
dc.contributor.authorMayoral-Varo, Victor
dc.contributor.authorMegias Vazquez, Diego 
dc.contributor.authorSanchez-Cabo, Fatima 
dc.contributor.authorDopazo, Ana 
dc.contributor.authorFerreira, Bibiana I
dc.contributor.authorLink, Wolfgang
dc.date.accessioned2021-07-15T11:04:08Z
dc.date.available2021-07-15T11:04:08Z
dc.date.issued2020-12-09
dc.identifier.citationCancers (Basel). 2020; 12(12):3689es_ES
dc.identifier.issn2072-6694es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/13243
dc.description.abstractTherapy resistance is responsible for most relapses in patients with cancer and is the major challenge to improving the clinical outcome. The pseudokinase Tribbles homologue 2 (TRIB2) has been characterized as an important driver of resistance to several anti-cancer drugs, including the dual ATP-competitive PI3K and mTOR inhibitor dactolisib (BEZ235). TRIB2 promotes AKT activity, leading to the inactivation of FOXO transcription factors, which are known to mediate the cell response to antitumor drugs. To characterize the downstream events of TRIB2 activity, we analyzed the gene expression profiles of isogenic cell lines with different TRIB2 statuses by RNA sequencing. Using a connectivity map-based computational approach, we identified drug-induced gene-expression profiles that invert the TRIB2-associated expression profile. In particular, the natural alkaloids harmine and piperlongumine not only produced inverse gene expression profiles but also synergistically increased BEZ235-induced cell toxicity. Importantly, both agents promote FOXO nuclear translocation without interfering with the nuclear export machinery and induce the transcription of FOXO target genes. Our results highlight the great potential of this approach for drug repurposing and suggest that harmine and piperlongumine or similar compounds might be useful in the clinic to overcome TRIB2-mediated therapy resistance in cancer patients.es_ES
dc.description.sponsorshipThis work was supported by the FUNDAÇÃO PARA A CIÊNCIA E TECNOLOGIA (FCT) Research Center Grant UID/BIM/04773/2013, Centre for Biomedical Research (CBMR), and by the Spanish Ministry of Science, Innovation and Universities through Grant RTI2018-094629-B-I00 to WL. B.I.F. was supported by FCT-SFRH/BPD/100434/2014 and the Marie Curie Individual Fellowship project TRIBBLES (#748585). This work was also supported by two LPCC-NRS/Terry Fox grants (2016/2017; 2017/2018). S. Machado is the recipient of a ProRegeM grant PD/BD/114258/2016. I. Duarte was supported by a scholarship from FCT Grant PTDC/BEX-BID/5410/2014es_ES
dc.language.isoenges_ES
dc.publisherMultidisciplinary Digital Publishing Institute (MDPI) es_ES
dc.type.hasVersionVoRes_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleHarmine and Piperlongumine Revert TRIB2-Mediated Drug Resistance.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID33316942es_ES
dc.format.volume12es_ES
dc.format.number12es_ES
dc.format.page3689es_ES
dc.identifier.doi10.3390/cancers12123689es_ES
dc.contributor.funderFundação para a Ciência e Tecnologia (Portugal) 
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España) 
dc.contributor.funderUnión Europea. Comisión Europea. H2020 
dc.description.peerreviewedes_ES
dc.identifier.journalCancerses_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Bioinformáticaes_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Genómicaes_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/H2020/748585es_ES
dc.rights.accessRightsopen accesses_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/RTI2018-094629-B-I00es_ES
dc.relation.projectFECYTinfo:eu-repo/grantAgreement/ES/FCT-SFRH/BPD/100434/2014es_ES


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