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TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT

2017-03Journal article Open Access
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dc.contributor.authorHill, Richard
dc.contributor.authorMadureira, Patricia
dc.contributor.authorFerreira, Bibiana
dc.contributor.authorBaptista, Inês
dc.contributor.authorMachado, S.
dc.contributor.authorColaco, Laura
dc.contributor.authordos Santos, Marta
dc.contributor.authorLiu, Ningshu
dc.contributor.authorDopazo, Ana
dc.contributor.authorUgurel, Selma
dc.contributor.authorAdrienn, Angyal
dc.contributor.authorKiss-Toth, Endre
dc.contributor.authorIsbilen, Murat
dc.contributor.authorGure, Ali O.
dc.contributor.authorLink, Wolfgang
dc.date.accessioned2018-12-07T14:53:38Z
dc.date.available2018-12-07T14:53:38Z
dc.date.issued2017-03
dc.description.abstractIntrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.
dc.identifier.doi10.1038/ncomms14687
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10400.1/11613
dc.language.isoeng
dc.peerreviewedyes
dc.publisherNature Publishing Group
dc.relationCharacterizing the clinical relevance of TRIB2 mediated resistance to PI3K pathway inhibition in colon and breast cancer
dc.relationIdentification and characterization of redox regulatory proteins involved in cancer progression
dc.relationCharacterization of TRIB2 mediated drug resistance and its validation as a novel diagnostic marker
dc.relationCentre for Biomedical Research
dc.subjectSignal-Transduction
dc.subjectMelanoma
dc.subjectPathway
dc.subjectCancer
dc.subjectCells
dc.subjectPhenotype
dc.subjectSurvival
dc.subjectAkt/Pkb
dc.subjectMdm2
dc.subjectFoxo
dc.titleTRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCharacterizing the clinical relevance of TRIB2 mediated resistance to PI3K pathway inhibition in colon and breast cancer
oaire.awardTitleIdentification and characterization of redox regulatory proteins involved in cancer progression
oaire.awardTitleCharacterization of TRIB2 mediated drug resistance and its validation as a novel diagnostic marker
oaire.awardTitleCentre for Biomedical Research
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F84634%2F2012/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBPD%2F100434%2F2014/PT
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oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F04773%2F2013/PT
oaire.citation.startPage14687
oaire.citation.titleNature Communications
oaire.citation.volume8
oaire.fundingStreamSFRH
oaire.fundingStreamOE
oaire.fundingStreamInvestigador FCT
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oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameHill
person.familyNameMadureira
person.familyNameferreira
person.familyNameMachado
person.familyNameLink
person.givenNameRichard
person.givenNamePatricia
person.givenNameBibiana
person.givenNameSusana
person.givenNameWolfgang
person.identifier803637
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person.identifier.orcid0000-0002-4856-3908
person.identifier.orcid0000-0003-4772-9395
person.identifier.orcid0000-0002-3152-1701
person.identifier.orcid0000-0002-3340-5165
person.identifier.ridK-4033-2012
person.identifier.scopus-author-id55266604200
person.identifier.scopus-author-id10340140500
person.identifier.scopus-author-id56201414700
person.identifier.scopus-author-id35368713800
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
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