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TNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cells

2020-02-12Journal article Open access
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dc.contributor.authorFaria, Márcia
dc.contributor.authorDomingues, Rita
dc.contributor.authorPaixão, Francisca
dc.contributor.authorBugalho, Maria João
dc.contributor.authorMatos, Paulo
dc.contributor.authorSilva, Ana Luísa
dc.date.accessioned2021-03-06T15:43:34Z
dc.date.available2021-03-06T15:43:34Z
dc.date.issued2020-02-12
dc.description.abstractThe 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.pt_PT
dc.description.sponsorshipThis 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPLoS One. 2020 Feb 12;15(2):e0228794. doi: 10.1371/journal.pone.0228794. eCollection 2020.pt_PT
dc.identifier.doi10.1371/journal.pone.0228794pt_PT
dc.identifier.issn1932-6203
dc.identifier.urihttp://hdl.handle.net/10400.18/7345
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherPublic Library of Sciencept_PT
dc.relationPTDC/BIAMOL/31787/2017pt_PT
dc.relationTargeting Rac1-signaling to enhance iodide-related cancer therapy
dc.relation.publisherversionhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228794pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectCell Linespt_PT
dc.subjectDose-Response Relationship, Drugpt_PT
dc.subjectNF-kappa Bpt_PT
dc.subjectSymporterspt_PT
dc.subjectThyroid Glandpt_PT
dc.subjectTumor Necrosis Factor-alphapt_PT
dc.subjectCancerpt_PT
dc.subjectTranscriptional Controlpt_PT
dc.subjectThyroid Carcinomapt_PT
dc.subjectSodium-iodide Symporterpt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titleTNFα-mediated activation of NF-κB downregulates sodium-iodide symporter expression in thyroid cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleTargeting Rac1-signaling to enhance iodide-related cancer therapy
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F114388%2F2016/PT
oaire.citation.issue2pt_PT
oaire.citation.startPagee0228794pt_PT
oaire.citation.titlePLoS ONEpt_PT
oaire.citation.volume15pt_PT
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com página web do editor da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication266a9c6d-196d-4e29-92fb-3b9df1f2cf64
relation.isProjectOfPublication.latestForDiscovery266a9c6d-196d-4e29-92fb-3b9df1f2cf64

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