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

Detalhes bibliográficos
Autor(a) principal: Faria, Márcia
Data de Publicação: 2021
Outros Autores: Domingues, Rita, Bugalho, Maria João, Matos, Paulo, Silva, Ana Luísa
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/50438
Resumo: © 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/).
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spelling MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cellsMAPK inhibitorsNISRAC1RAI therapyRadioiodide uptakethyroid cancer© 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/).The 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.This 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.MDPIRepositório da Universidade de LisboaFaria, MárciaDomingues, RitaBugalho, Maria JoãoMatos, PauloSilva, Ana Luísa2021-12-16T15:22:49Z20212021-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/50438engCancers (Basel). 2021 Nov 22;13(22):586110.3390/cancers132258612072-6694info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:54:37Zoai:repositorio.ul.pt:10451/50438Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:01:53.695721Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cells
title MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cells
spellingShingle MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cells
Faria, Márcia
MAPK inhibitors
NIS
RAC1
RAI therapy
Radioiodide uptake
thyroid cancer
title_short MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cells
title_full MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cells
title_fullStr MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cells
title_full_unstemmed MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cells
title_sort MAPK inhibition requires active RAC1 signaling to effectively improve iodide uptake by thyroid follicular cells
author Faria, Márcia
author_facet Faria, Márcia
Domingues, Rita
Bugalho, Maria João
Matos, Paulo
Silva, Ana Luísa
author_role author
author2 Domingues, Rita
Bugalho, Maria João
Matos, Paulo
Silva, Ana Luísa
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Repositório da Universidade de Lisboa
dc.contributor.author.fl_str_mv Faria, Márcia
Domingues, Rita
Bugalho, Maria João
Matos, Paulo
Silva, Ana Luísa
dc.subject.por.fl_str_mv MAPK inhibitors
NIS
RAC1
RAI therapy
Radioiodide uptake
thyroid cancer
topic MAPK inhibitors
NIS
RAC1
RAI therapy
Radioiodide uptake
thyroid cancer
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/).
publishDate 2021
dc.date.none.fl_str_mv 2021-12-16T15:22:49Z
2021
2021-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10451/50438
url http://hdl.handle.net/10451/50438
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Cancers (Basel). 2021 Nov 22;13(22):5861
10.3390/cancers13225861
2072-6694
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
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instacron_str RCAAP
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reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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