MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells

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 diseas...

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Autores principales:	Márcia Faria, Rita Domingues, Maria João Bugalho, Paulo Matos, Ana Luísa Silva
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	NIS RAC1 thyroid cancer radioiodide uptake RAI therapy MAPK inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/1326c3cbde884a68b08ba9f2e8b09ff1
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spelling	oai:doaj.org-article:1326c3cbde884a68b08ba9f2e8b09ff12021-11-25T17:04:49ZMAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells10.3390/cancers132258612072-6694https://doaj.org/article/1326c3cbde884a68b08ba9f2e8b09ff12021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5861https://doaj.org/toc/2072-6694The 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.Márcia FariaRita DominguesMaria João BugalhoPaulo MatosAna Luísa SilvaMDPI AGarticleNISRAC1thyroid cancerradioiodide uptakeRAI therapyMAPK inhibitorsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5861, p 5861 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	NIS RAC1 thyroid cancer radioiodide uptake RAI therapy MAPK inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	NIS RAC1 thyroid cancer radioiodide uptake RAI therapy MAPK inhibitors Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Márcia Faria Rita Domingues Maria João Bugalho Paulo Matos Ana Luísa Silva MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells
description	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.
format	article
author	Márcia Faria Rita Domingues Maria João Bugalho Paulo Matos Ana Luísa Silva
author_facet	Márcia Faria Rita Domingues Maria João Bugalho Paulo Matos Ana Luísa Silva
author_sort	Márcia Faria
title	MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells
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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1326c3cbde884a68b08ba9f2e8b09ff1
work_keys_str_mv	AT marciafaria mapkinhibitionrequiresactiverac1signalingtoeffectivelyimproveiodideuptakebythyroidfollicularcells AT ritadomingues mapkinhibitionrequiresactiverac1signalingtoeffectivelyimproveiodideuptakebythyroidfollicularcells AT mariajoaobugalho mapkinhibitionrequiresactiverac1signalingtoeffectivelyimproveiodideuptakebythyroidfollicularcells AT paulomatos mapkinhibitionrequiresactiverac1signalingtoeffectivelyimproveiodideuptakebythyroidfollicularcells AT analuisasilva mapkinhibitionrequiresactiverac1signalingtoeffectivelyimproveiodideuptakebythyroidfollicularcells
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MAPK Inhibition Requires Active RAC1 Signaling to Effectively Improve Iodide Uptake by Thyroid Follicular Cells

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