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Harmine and Piperlongumine revert TRIB2-mediated drug resistance

2020Journal article Open Access
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dc.contributor.authorMachado, Susana
dc.contributor.authorSilva, Andreia
dc.contributor.authorDe Sousa-Coelho, Ana LuĂ­sa
dc.contributor.authorDuarte, Isabel
dc.contributor.authorGrenho, InĂȘs
dc.contributor.authorSantos, Bruno F
dc.contributor.authorMayoral-Varo, Victor
dc.contributor.authorMegias, Diego
dc.contributor.authorSĂĄnchez-Cabo, FĂĄtima
dc.contributor.authorDopazo, Ana
dc.contributor.authorFerreira, Bibiana I.
dc.contributor.authorLink, Wolfgang
dc.date.accessioned2021-01-13T17:12:53Z
dc.date.available2021-01-13T17:12:53Z
dc.date.issued2020
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.pt_PT
dc.description.sponsorshipFCT: PTDC/BEX-BID/5410/2014/ FCT-SFRH/BPD/100434/2014pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.3390/cancers12123689pt_PT
dc.identifier.eissn2072-6694
dc.identifier.urihttp://hdl.handle.net/10400.1/14958
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationCharacterizing the clinical relevance and the mechanism underlying TRIB2-mediated drug resistance to MEK inhibitiors in the context of melanoma
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectTRIB2pt_PT
dc.subjectFOXOpt_PT
dc.subjectPiperlonguminept_PT
dc.subjectDrug resistancept_PT
dc.subjectCancerpt_PT
dc.subjectBEZ235pt_PT
dc.subjectHarminept_PT
dc.titleHarmine and Piperlongumine revert TRIB2-mediated drug resistancept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCharacterizing the clinical relevance and the mechanism underlying TRIB2-mediated drug resistance to MEK inhibitiors in the context of melanoma
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FBIM%2F04773%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/748585/EU
oaire.citation.issue12pt_PT
oaire.citation.startPage3689pt_PT
oaire.citation.titleCancerspt_PT
oaire.citation.volume12pt_PT
oaire.fundingStream5876
oaire.fundingStreamH2020
person.familyNameMachado
person.familyNameDe Sousa-Coelho
person.familyNamedos Santos Duarte
person.familyNameGrenho
person.familyNameda Silva Santos
person.givenNameSusana
person.givenNameAna LuĂ­sa
person.givenNameGuilhermina Isabel
person.givenNameInĂȘs
person.givenNameBruno Filipe
person.identifier.ciencia-id691B-A574-28ED
person.identifier.ciencia-idED15-7F67-7B64
person.identifier.ciencia-id7012-6BCC-CC65
person.identifier.ciencia-id9F19-3184-159F
person.identifier.orcid0000-0002-3152-1701
person.identifier.orcid0000-0002-8451-4302
person.identifier.orcid0000-0003-0060-2936
person.identifier.orcid0000-0003-3777-9380
person.identifier.ridK-4033-2012
person.identifier.scopus-author-id56201414700
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameFundação para a CiĂȘncia e a Tecnologia
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublicationc7b0d14f-ae71-45a3-bce1-6dcd1fc66f67
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