MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.18/7925 |
Resumo: | This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis |
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MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular CellsThyroid CancerNISRAC1Radioiodide UptakeRAI TherapyMAPK InhibitorsGTPase SignalingTumorigenesisVias de Transdução de Sinal e Patologias AssociadasThis article belongs to the Special Issue Role of Small GTPase Signaling in TumorigenesisThe 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 Científico do Instituto Nacional de SaúdeFaria, MárciaDomingues, RitaBugalho, Maria JoãoMatos, PauloSilva, Ana Luísa2022-02-03T17:07:53Z2021-11-222021-11-22T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/7925engCancers (Basel). 2021 Nov 22;13(22):5861. doi: 10.3390/cancers132258612072-669410.3390/cancers13225861info: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:RCAAP2023-07-20T15:42:19Zoai:repositorio.insa.pt:10400.18/7925Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:42:36.359697Repositório 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 Thyroid Cancer NIS RAC1 Radioiodide Uptake RAI Therapy MAPK Inhibitors GTPase Signaling Tumorigenesis Vias de Transdução de Sinal e Patologias Associadas |
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 Científico do Instituto Nacional de Saúde |
dc.contributor.author.fl_str_mv |
Faria, Márcia Domingues, Rita Bugalho, Maria João Matos, Paulo Silva, Ana Luísa |
dc.subject.por.fl_str_mv |
Thyroid Cancer NIS RAC1 Radioiodide Uptake RAI Therapy MAPK Inhibitors GTPase Signaling Tumorigenesis Vias de Transdução de Sinal e Patologias Associadas |
topic |
Thyroid Cancer NIS RAC1 Radioiodide Uptake RAI Therapy MAPK Inhibitors GTPase Signaling Tumorigenesis Vias de Transdução de Sinal e Patologias Associadas |
description |
This article belongs to the Special Issue Role of Small GTPase Signaling in Tumorigenesis |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-11-22 2021-11-22T00:00:00Z 2022-02-03T17:07:53Z |
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/10400.18/7925 |
url |
http://hdl.handle.net/10400.18/7925 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Cancers (Basel). 2021 Nov 22;13(22):5861. doi: 10.3390/cancers13225861 2072-6694 10.3390/cancers13225861 |
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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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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