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MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cells

2021Journal article Open access
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dc.contributor.authorFaria, Márcia
dc.contributor.authorDomingues, Rita
dc.contributor.authorBugalho, Maria João
dc.contributor.authorMatos, Paulo
dc.contributor.authorSilva, Ana Luísa
dc.date.accessioned2021-12-16T15:22:49Z
dc.date.available2021-12-16T15:22:49Z
dc.date.issued2021
dc.description© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).pt_PT
dc.description.abstractThe Sodium/Iodide Symporter (NIS) is responsible for the active transport of iodide into thyroid follicular cells. Differentiated thyroid carcinomas (DTCs) usually preserve the functional expression of NIS, allowing the use of radioactive iodine (RAI) as the treatment of choice for metastatic disease. However, a significant proportion of patients with advanced forms of TC become refractory to RAI therapy and no effective therapeutic alternatives are available. Impaired iodide uptake is mainly caused by the defective functional expression of NIS, and this has been associated with several pathways linked to malignant transformation. MAPK signaling has emerged as one of the main pathways implicated in thyroid tumorigenesis, and its overactivation has been associated with the downregulation of NIS expression. Thus, several strategies have been developed to target the MAPK pathway attempting to increase iodide uptake in refractory DTC. However, MAPK inhibitors have had only partial success in restoring NIS expression and, in most cases, it remained insufficient to allow effective treatment with RAI. In a previous work, we have shown that the activity of the small GTPase RAC1 has a positive impact on TSH-induced NIS expression and iodide uptake in thyroid cells. RAC1 is a downstream effector of NRAS, but not of BRAF. Therefore, we hypothesized that the positive regulation induced by RAC1 on NIS could be a relevant signaling cue in the mechanism underlying the differential response to MEK inhibitors, observed between NRAS- and BRAF-mutant tumors. In the present study, we found that the recovery of NIS expression induced through MAPK pathway inhibition can be enhanced by potentiating RAC1 activity in thyroid cell systems. The negative impact on NIS expression induced by the MAPK-activating alterations, NRAS Q61R and BRAF V600E, was partially reversed by the presence of the MEK 1/2 inhibitors AZD6244 and CH5126766. Notably, the inhibition of RAC1 signaling partially blocked the positive impact of MEK inhibition on NIS expression in NRAS Q61R cells. Conversely, the presence of active RAC1 considerably improved the rescue of NIS expression in BRAF V600E thyroid cells treated with MEK inhibitors. Overall, our data support an important role for RAC1 signaling in enhancing MAPK inhibition in the context of RAI therapy in DTC, opening new opportunities for therapeutic intervention.pt_PT
dc.description.sponsorshipThis work was funded by Bolsa Prof. Edward Limbert Merck/SPEDM/2021 (from Merk/SPEDM, Portugal) and the Fundação para a Ciência e a Tecnologia (FCT), Portugal, through grants PTDC/BIAMOL/31787/2017 (to ALS and PM) and UID/MULTI/04046/2019 (to BioISI). M.F. was a recipient of the FCT fellowship PD/BD/114388/2016 within the BioSYS PhD program from BioISI.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCancers (Basel). 2021 Nov 22;13(22):5861pt_PT
dc.identifier.doi10.3390/cancers13225861pt_PT
dc.identifier.eissn2072-6694
dc.identifier.urihttp://hdl.handle.net/10451/50438
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationPTDC/BIAMOL/31787/2017pt_PT
dc.relationBiosystems & Integrative Sciences Institute
dc.relationTargeting Rac1-signaling to enhance iodide-related cancer therapy
dc.relation.publisherversionhttps://www.mdpi.com/journal/cancerspt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectMAPK inhibitorspt_PT
dc.subjectNISpt_PT
dc.subjectRAC1pt_PT
dc.subjectRAI therapypt_PT
dc.subjectRadioiodide uptakept_PT
dc.subjectthyroid cancerpt_PT
dc.titleMAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleBiosystems & Integrative Sciences Institute
oaire.awardTitleTargeting Rac1-signaling to enhance iodide-related cancer therapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04046%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F114388%2F2016/PT
oaire.citation.issue22pt_PT
oaire.citation.titleCancerspt_PT
oaire.citation.volume13pt_PT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameFaria
person.familyNameCardoso Domingues
person.familyNameBugalho
person.familyNameSilva
person.givenNameMárcia
person.givenNameRita Sofia
person.givenNameMaria João
person.givenNameAna Luísa
person.identifier1596200
person.identifierF-5245-2012
person.identifier.ciencia-id0B12-EF2F-133D
person.identifier.ciencia-idD51C-30D5-71FC
person.identifier.ciencia-id0F14-CA4F-1358
person.identifier.ciencia-idD215-714A-CA06
person.identifier.orcid0000-0002-6601-1138
person.identifier.orcid0000-0001-7130-3795
person.identifier.orcid0000-0003-0357-7350
person.identifier.orcid0000-0002-9379-9696
person.identifier.orcid0000-0002-4839-8279
person.identifier.scopus-author-id35582359500
person.identifier.scopus-author-id7003265109
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.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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