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Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells

SIMPLE SUMMARY: Most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis. However, a significant number progress to advanced disease exhibiting aggressive clinical characteristics. These cases have a poorer prognosis because they become resistant to radioactive iodin...

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Autores principales: Faria, Márcia, Vareda, José, Miranda, Micaella, Bugalho, Maria João, Silva, Ana Luísa, Matos, Paulo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9659096/
https://www.ncbi.nlm.nih.gov/pubmed/36358781
http://dx.doi.org/10.3390/cancers14215362
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author Faria, Márcia
Vareda, José
Miranda, Micaella
Bugalho, Maria João
Silva, Ana Luísa
Matos, Paulo
author_facet Faria, Márcia
Vareda, José
Miranda, Micaella
Bugalho, Maria João
Silva, Ana Luísa
Matos, Paulo
author_sort Faria, Márcia
collection PubMed
description SIMPLE SUMMARY: Most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis. However, a significant number progress to advanced disease exhibiting aggressive clinical characteristics. These cases have a poorer prognosis because they become resistant to radioactive iodine (RAI) treatment. One of the causes for this resistance is the reduction of the channel responsible for iodide uptake (NIS—the sodium iodide symporter) at the plasma membrane (PM) of metastatic thyroid cancer cells. Here we describe that cell–cell adhesion is a key determinant for NIS residency at the PM, suggesting that loss of cell–cell adhesion during metastization contributes to RAI treatment resistance in advanced TC. Our findings indicate that successful resensitization therapies might require the use of agents that improve epithelial cell–cell adhesion in refractory TC cells. ABSTRACT: While most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis, a significant number progress to advanced disease exhibiting aggressive clinical characteristics and often becoming refractory to radioactive iodine (RAI) treatment, the current gold-standard therapeutic option for metastatic disease. RAI-refractoriness is caused by defective functional expression of the sodium-iodide symporter (NIS), which is responsible for the active transport of iodide across the plasma membrane (PM) into thyroid follicles. NIS deficiency in these tumors often reflects a transcriptional impairment, but also its defective targeting and retention at the cells’ PM. Using proteomics, we previously characterized an intracellular signaling pathway derived from SRC kinase that acts through the small GTPase RAC1 to recruit and bind the actin-anchoring adaptor EZRIN to NIS, regulating its retention at the PM of both non-transformed and cancer thyroid cells. Here, we describe how by reanalyzing the proteomics data, we identified cell–cell adhesion as the molecular event upstream the pathway involved in the anchoring and retention at the PM. We show that by interacting with NIS at the PM, adherens junction (AJ)-associated P120-catenin recruits and is phosphorylated by SRC, allowing it to recruit RAC1 to the complex. This enables SRC-phosphorylated VAV2 exchange factor to activate RAC1 GTPase, inducing NIS retention at the PM, thus increasing its abundance and function at the surface of thyroid cells. Our findings indicate that the loss of epithelial cell–cell adhesion may contribute to RAI refractoriness, indicating that in addition to stimulating NIS expression, successful resensitization therapies might require the employment of agents that improve cell–cell adhesion and NIS PM retention in refractory TC cells.
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spelling pubmed-96590962022-11-15 Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells Faria, Márcia Vareda, José Miranda, Micaella Bugalho, Maria João Silva, Ana Luísa Matos, Paulo Cancers (Basel) Article SIMPLE SUMMARY: Most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis. However, a significant number progress to advanced disease exhibiting aggressive clinical characteristics. These cases have a poorer prognosis because they become resistant to radioactive iodine (RAI) treatment. One of the causes for this resistance is the reduction of the channel responsible for iodide uptake (NIS—the sodium iodide symporter) at the plasma membrane (PM) of metastatic thyroid cancer cells. Here we describe that cell–cell adhesion is a key determinant for NIS residency at the PM, suggesting that loss of cell–cell adhesion during metastization contributes to RAI treatment resistance in advanced TC. Our findings indicate that successful resensitization therapies might require the use of agents that improve epithelial cell–cell adhesion in refractory TC cells. ABSTRACT: While most cases of differentiated thyroid carcinoma (DTC) are associated with a good prognosis, a significant number progress to advanced disease exhibiting aggressive clinical characteristics and often becoming refractory to radioactive iodine (RAI) treatment, the current gold-standard therapeutic option for metastatic disease. RAI-refractoriness is caused by defective functional expression of the sodium-iodide symporter (NIS), which is responsible for the active transport of iodide across the plasma membrane (PM) into thyroid follicles. NIS deficiency in these tumors often reflects a transcriptional impairment, but also its defective targeting and retention at the cells’ PM. Using proteomics, we previously characterized an intracellular signaling pathway derived from SRC kinase that acts through the small GTPase RAC1 to recruit and bind the actin-anchoring adaptor EZRIN to NIS, regulating its retention at the PM of both non-transformed and cancer thyroid cells. Here, we describe how by reanalyzing the proteomics data, we identified cell–cell adhesion as the molecular event upstream the pathway involved in the anchoring and retention at the PM. We show that by interacting with NIS at the PM, adherens junction (AJ)-associated P120-catenin recruits and is phosphorylated by SRC, allowing it to recruit RAC1 to the complex. This enables SRC-phosphorylated VAV2 exchange factor to activate RAC1 GTPase, inducing NIS retention at the PM, thus increasing its abundance and function at the surface of thyroid cells. Our findings indicate that the loss of epithelial cell–cell adhesion may contribute to RAI refractoriness, indicating that in addition to stimulating NIS expression, successful resensitization therapies might require the employment of agents that improve cell–cell adhesion and NIS PM retention in refractory TC cells. MDPI 2022-10-31 /pmc/articles/PMC9659096/ /pubmed/36358781 http://dx.doi.org/10.3390/cancers14215362 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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/).
spellingShingle Article
Faria, Márcia
Vareda, José
Miranda, Micaella
Bugalho, Maria João
Silva, Ana Luísa
Matos, Paulo
Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells
title Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells
title_full Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells
title_fullStr Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells
title_full_unstemmed Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells
title_short Adherens Junction Integrity Is a Critical Determinant of Sodium Iodide Symporter Residency at the Plasma Membrane of Thyroid Cells
title_sort adherens junction integrity is a critical determinant of sodium iodide symporter residency at the plasma membrane of thyroid cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9659096/
https://www.ncbi.nlm.nih.gov/pubmed/36358781
http://dx.doi.org/10.3390/cancers14215362
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