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Ibuprofen disrupts a WNK1/GSK3β/SRPK1 protein complex required for expression of tumor-related splicing variant RAC1B in colorectal cells

2020-11-24Journal article Open access
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dc.contributor.authorGonçalves, Vânia
dc.contributor.authorHenriques, Andreia F.A.
dc.contributor.authorMatos, Paulo
dc.contributor.authorJordan, Peter
dc.date.accessioned2021-03-15T16:00:15Z
dc.date.available2021-03-15T16:00:15Z
dc.date.issued2020-11-24
dc.description.abstractA major risk factor promoting tumor development is chronic inflammation and the use of nonsteroidal anti-inflammatory drugs (NSAID), including ibuprofen, can decrease the risk of developing various types of cancer, including colorectal cancer (CRC). Although the molecular mechanism behind the antitumor properties of NSAIDs has been largely attributed to inhibition of cyclooxygenases (COXs), several studies have shown that the chemopreventive properties of ibuprofen also involve multiple COX-independent effects. One example is its ability to inhibit the alternative splicing event generating RAC1B, which is overexpressed in a specific subset of BRAF-mutated colorectal tumors and sustains cell survival. Here we describe the mechanism by which ibuprofen prevents RAC1B alternative splicing in a BRAF mutant CRC cell line: it leads to decreased translocation of SRPK1 and SRSF1 to the nucleus and is regulated by a WNK1/GSK3β/SRPK1 protein kinase complex. Surprisingly, we demonstrate that ibuprofen does not inhibit the activity of any of the involved kinases but rather promotes disassembly of this regulatory complex, exposing GSK3β serine 9 to inhibitory phosphorylation, namely by AKT, which results in nuclear exclusion of SRPK1 and SRSF1 hypophosphorylation. The data shed new light on the biochemical mechanisms behind ibuprofen's action on alternative spliced RAC1B and may support its use in personalized approaches to CRC therapy or chemoprevention regimens.pt_PT
dc.description.sponsorshipThis work was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal (through grants UID/MULTI/04046/2019 to Research Unit BioISI and PTDC/BIA-MOL/28386/2017 to VG, as well as fellowship SFRH/BD/106080/2015 from the BioSys PhD program PD65-2012 to AFH, and contract ‘FCT Investigator’ to PM) and by the Portuguese association Maratona da Saúde — Cancro 2014 to PJ.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationOncotarget. 2020 Nov 24;11(47):4421-4437. doi: 10.18632/oncotarget.27816pt_PT
dc.identifier.doi10.18632/oncotarget.27816pt_PT
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/10400.18/7498
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherImpact Journalspt_PT
dc.relationSFRH/BD/106080/2015pt_PT
dc.relationMicroenvironmental effects on alternative splicing in malignant progression of colorectal tumor cells
dc.relationBiosystems & Integrative Sciences Institute
dc.relation.publisherversionhttps://www.oncotarget.com/article/27816/text/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectIbuprofenpt_PT
dc.subjectRAC1Bpt_PT
dc.subjectAlternative Splicingpt_PT
dc.subjectColorectal Cancer Cellspt_PT
dc.subjectProtein Kinasept_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.subjectCancro Colorectalpt_PT
dc.subjectsplicing Alternativopt_PT
dc.titleIbuprofen disrupts a WNK1/GSK3β/SRPK1 protein complex required for expression of tumor-related splicing variant RAC1B in colorectal cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMicroenvironmental effects on alternative splicing in malignant progression of colorectal tumor cells
oaire.awardTitleBiosystems & Integrative Sciences Institute
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-MOL%2F28386%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04046%2F2019/PT
oaire.citation.endPage4437pt_PT
oaire.citation.issue47pt_PT
oaire.citation.startPage4421pt_PT
oaire.citation.titleOncotargetpt_PT
oaire.citation.volume11pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
project.funder.identifierhttp://doi.org/10.13039/501100001871
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
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication04d4989e-a18e-4287-bc19-a3d9ee1c7430
relation.isProjectOfPublication35168786-8dfc-4a00-9759-dab3669fe1ae
relation.isProjectOfPublication.latestForDiscovery04d4989e-a18e-4287-bc19-a3d9ee1c7430

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