TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells
Autor(a) principal: | |
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Data de Publicação: | 2020 |
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/10400.18/7345 |
Resumo: | The sodium-iodide symporter (NIS) mediates transport of iodide across the basolateral membrane of thyroid cells. NIS expression in thyroid cancer (TC) cells allows the use of radioactive iodine (RAI) as a diagnostic and therapeutic tool, being RAI therapy the systemic treatment of choice for metastatic disease. Still, a significant proportion of patients with advanced TC lose the ability to respond to RAI therapy and no effective alternative therapies are available. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. NF-κB signaling is one of the pathways associated with TC. Interestingly, NIS expression can be negatively regulated by TNF-α, a bona fide activator of NF-κB with a central role in thyroid autoimmunity. This prompted us to clarify NF-kB's role in this process. We confirmed that TNF-α leads to downregulation of TSH-induced NIS expression in non-neoplastic thyroid follicular cell-derived models. Notably, a similar effect was observed when NF-κB activation was triggered independently of ligand-receptor specificity, using phorbol-myristate-acetate (PMA). TNF-α and PMA downregulation of NIS expression was reverted when NF-κB-dependent transcription was blocked, demonstrating the requirement for NF-kB activity. Additionally, TNF-α and PMA were shown to have a negative impact on TSH-induced iodide uptake, consistent with the observed transcriptional downregulation of NIS. Our data support the involvement of NF-κB-directed transcription in the modulation of NIS expression, where up- or down-regulation of NIS depends on the combined output to NF-κB of several converging pathways. A better understanding of the mechanisms underlying NIS expression in the context of normal thyroid physiology may guide the development of pharmacological strategies to increase the efficiency of iodide uptake. Such strategies would be extremely useful in improving the response to RAI therapy in refractory-TC. |
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TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cellsCell LinesDose-Response Relationship, DrugNF-kappa BSymportersThyroid GlandTumor Necrosis Factor-alphaCancerTranscriptional ControlThyroid CarcinomaSodium-iodide SymporterVias de Transdução de Sinal e Patologias AssociadasThe sodium-iodide symporter (NIS) mediates transport of iodide across the basolateral membrane of thyroid cells. NIS expression in thyroid cancer (TC) cells allows the use of radioactive iodine (RAI) as a diagnostic and therapeutic tool, being RAI therapy the systemic treatment of choice for metastatic disease. Still, a significant proportion of patients with advanced TC lose the ability to respond to RAI therapy and no effective alternative therapies are available. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. NF-κB signaling is one of the pathways associated with TC. Interestingly, NIS expression can be negatively regulated by TNF-α, a bona fide activator of NF-κB with a central role in thyroid autoimmunity. This prompted us to clarify NF-kB's role in this process. We confirmed that TNF-α leads to downregulation of TSH-induced NIS expression in non-neoplastic thyroid follicular cell-derived models. Notably, a similar effect was observed when NF-κB activation was triggered independently of ligand-receptor specificity, using phorbol-myristate-acetate (PMA). TNF-α and PMA downregulation of NIS expression was reverted when NF-κB-dependent transcription was blocked, demonstrating the requirement for NF-kB activity. Additionally, TNF-α and PMA were shown to have a negative impact on TSH-induced iodide uptake, consistent with the observed transcriptional downregulation of NIS. Our data support the involvement of NF-κB-directed transcription in the modulation of NIS expression, where up- or down-regulation of NIS depends on the combined output to NF-κB of several converging pathways. A better understanding of the mechanisms underlying NIS expression in the context of normal thyroid physiology may guide the development of pharmacological strategies to increase the efficiency of iodide uptake. Such strategies would be extremely useful in improving the response to RAI therapy in refractory-TC.This work was supported by the Fundação para a Ciência e a Tecnologia, grant [PTDC/BIAMOL/31787/2017] from Portugal. MF is recipient of FCT fellowship PD/BD/114388/2016.Public Library of ScienceRepositório Científico do Instituto Nacional de SaúdeFaria, MárciaDomingues, RitaPaixão, FranciscaBugalho, Maria JoãoMatos, PauloSilva, Ana Luísa2021-03-06T15:43:34Z2020-02-122020-02-12T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.18/7345engPLoS One. 2020 Feb 12;15(2):e0228794. doi: 10.1371/journal.pone.0228794. eCollection 2020.1932-620310.1371/journal.pone.0228794info: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:RCAAP2023-07-20T15:41:54Zoai:repositorio.insa.pt:10400.18/7345Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:41:55.469121Repositório 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 |
TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells |
title |
TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells |
spellingShingle |
TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells Faria, Márcia Cell Lines Dose-Response Relationship, Drug NF-kappa B Symporters Thyroid Gland Tumor Necrosis Factor-alpha Cancer Transcriptional Control Thyroid Carcinoma Sodium-iodide Symporter Vias de Transdução de Sinal e Patologias Associadas |
title_short |
TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells |
title_full |
TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells |
title_fullStr |
TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells |
title_full_unstemmed |
TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells |
title_sort |
TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells |
author |
Faria, Márcia |
author_facet |
Faria, Márcia Domingues, Rita Paixão, Francisca Bugalho, Maria João Matos, Paulo Silva, Ana Luísa |
author_role |
author |
author2 |
Domingues, Rita Paixão, Francisca Bugalho, Maria João Matos, Paulo Silva, Ana Luísa |
author2_role |
author 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 Paixão, Francisca Bugalho, Maria João Matos, Paulo Silva, Ana Luísa |
dc.subject.por.fl_str_mv |
Cell Lines Dose-Response Relationship, Drug NF-kappa B Symporters Thyroid Gland Tumor Necrosis Factor-alpha Cancer Transcriptional Control Thyroid Carcinoma Sodium-iodide Symporter Vias de Transdução de Sinal e Patologias Associadas |
topic |
Cell Lines Dose-Response Relationship, Drug NF-kappa B Symporters Thyroid Gland Tumor Necrosis Factor-alpha Cancer Transcriptional Control Thyroid Carcinoma Sodium-iodide Symporter Vias de Transdução de Sinal e Patologias Associadas |
description |
The sodium-iodide symporter (NIS) mediates transport of iodide across the basolateral membrane of thyroid cells. NIS expression in thyroid cancer (TC) cells allows the use of radioactive iodine (RAI) as a diagnostic and therapeutic tool, being RAI therapy the systemic treatment of choice for metastatic disease. Still, a significant proportion of patients with advanced TC lose the ability to respond to RAI therapy and no effective alternative therapies are available. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. NF-κB signaling is one of the pathways associated with TC. Interestingly, NIS expression can be negatively regulated by TNF-α, a bona fide activator of NF-κB with a central role in thyroid autoimmunity. This prompted us to clarify NF-kB's role in this process. We confirmed that TNF-α leads to downregulation of TSH-induced NIS expression in non-neoplastic thyroid follicular cell-derived models. Notably, a similar effect was observed when NF-κB activation was triggered independently of ligand-receptor specificity, using phorbol-myristate-acetate (PMA). TNF-α and PMA downregulation of NIS expression was reverted when NF-κB-dependent transcription was blocked, demonstrating the requirement for NF-kB activity. Additionally, TNF-α and PMA were shown to have a negative impact on TSH-induced iodide uptake, consistent with the observed transcriptional downregulation of NIS. Our data support the involvement of NF-κB-directed transcription in the modulation of NIS expression, where up- or down-regulation of NIS depends on the combined output to NF-κB of several converging pathways. A better understanding of the mechanisms underlying NIS expression in the context of normal thyroid physiology may guide the development of pharmacological strategies to increase the efficiency of iodide uptake. Such strategies would be extremely useful in improving the response to RAI therapy in refractory-TC. |
publishDate |
2020 |
dc.date.none.fl_str_mv |
2020-02-12 2020-02-12T00:00:00Z 2021-03-06T15:43:34Z |
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/10400.18/7345 |
url |
http://hdl.handle.net/10400.18/7345 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
PLoS One. 2020 Feb 12;15(2):e0228794. doi: 10.1371/journal.pone.0228794. eCollection 2020. 1932-6203 10.1371/journal.pone.0228794 |
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 |
Public Library of Science |
publisher.none.fl_str_mv |
Public Library of Science |
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 |
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RCAAP |
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RCAAP |
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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) |
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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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