An Inverse Agonist of Estrogen-Related Receptor Gamma, GSK5182, Enhances Na+/I− Symporter Function in Radioiodine-Refractory Papillary Thyroid Cancer Cells

Sep 24, 2026

An inverse agonist of estrogen-related receptor gamma (ERRα), GSK5182, is investigated for its ability to improve sodium iodide (Na+/I−) symporter (NIS) function in papillary thyroid cancer resistant to radioactive iodine (RAI). RAI-refractory BCPAP cells were exposed to GSK5182 for 24 h across concentrations, and radioiodine avidity was measured with or without the NIS inhibitor potassium perchlorate. GSK5182 increased radioiodine uptake dose-dependently, with ERRα downregulation and ERK1/2 phosphorylation, raising total and membrane NIS and iodide metabolism-related gene expression. MEK inhibition reversed the GSK5182 effect, and the combination of GSK5182 with I-131 produced the lowest clonogenic survival.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Abstract

Introduction

NIS and radioactive iodine in thyroid cancer

Downregulation and resistance mechanisms in PTC

Estrogen-related receptors and ERRα background

cells Article An Inverse Agonist of Estrogen-Related Receptor Gamma, GSK5182, Enhances Na+/I 􀀀 Symporter Function in Radioiodine-Refractory Papillary Thyroid Cancer Cells Thoudam Debraj Singh 1, *,†, Jae Eon Lee 2,†, Kwang Hee Son 2, Bo Ra Lee 2, Sang Kyoon Kim 2, Deepak Gulwani 1, Vijaya Sarangthem 3 and Yong Hyun Jeon 2, * Citation: Singh, T.D.; Lee, J.E.; Son, K.H.; Lee, B.R.; Kim, S.K.; Gulwani, D.; Sarangthem, V.; Jeon, Y.H. An Inverse Agonist of Estrogen-Related Receptor Gamma, GSK5182, Enhances Na+ /I 􀀀 Symporter Function in Radioiodine-Refractory Papillary Thyroid Cancer Cells. Cells 2023, 12, 470. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/cells12030470](10.3390/cells12030470) Academic Editor: Wolfgang Sauerwein Received: 30 November 2022 Revised: 2 January 2023 Accepted: 30 January 2023 Published: 1 February 2023 1 Department of Medical Oncology Lab, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India 2 Preclincial Research Center (PRL), Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, Republic of Korea 3 Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India * Correspondence: [debraj.thoudam@gmail.com](debraj.thoudam@gmail.com) (T.D.S.); [jeon9014@gmail.com](jeon9014@gmail.com) (Y.-H.J.)† These authors contributed equally to this work. Abstract: Previously, we reported that an inverse agonist of estrogen-related receptor gamma (ERR􀀍), GSK5182, enhances sodium iodide (Na+ /I 􀀀 ) symporter (NIS) function through mitogen-activated protein (MAP) kinase signaling in anaplastic thyroid cancer cells. This ﬁnding helped us to further investigate the effects of GSK5182 on NIS function in papillary thyroid cancer (PTC) refractory to radioactive iodine (RAI) therapy. Herein, we report the effects of ERR􀀍 on the regulation of NIS function in RAI-resistant PTC cells using GSK5182 . RAI-refractory BCPAP cells were treated with GK5182 for 24 h at various concentrations, and radioiodine avidity was determined with or without potassium perchlorate (KClO 4) as an NIS inhibitor. We explored the effects of GSK5182 on ERR􀀍, the mitogen-activated protein (MAP) kinase pathway, and iodide metabolism-related genes. We examined whether the MAP pathway affected GSK5182-mediated NIS function using U0126, a selective MEK inhibitor. A clonogenic assay was performed to evaluate the cytotoxic effects of I-131 . GSK5182 induced an increase in radioiodine avidity in a dose-dependent manner, and the enhanced uptake was completely inhibited by KClO 4 in BCPAP cells. We found that ERR􀀍 was downregulated and phosphorylated extracellular signal-regulated kinase (ERK)1/2 was upregulated in BCPAP cells, with an increase in total and membranous NIS and iodide metabolism-related genes. MEK inhibitors reversed the increase in radioiodine avidity induced by GSK5182 . Clonogenic examination revealed the lowest survival in cells treated with a combination of GSK5182 and I-131 compared to those treated with either GSK518 or I-131 alone. We demonstrate that an inverse agonist of ERR􀀍, GSK5182, enhances the function of NIS protein via the modulation of ERR􀀍 and MAP kinase signaling, thereby leading to increased responsiveness to radioiodine in RAI-refractory papillary thyroid cancer cells. Keywords: estrogen-related receptor gamma; radioiodine-refractory papillary thyroid cancer cells; sodium iodide symporter; radioiodine uptake; radioiodine therapy Copyright: © 2023 by the authors. 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://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1. Introduction The sodium iodide (Na+ /I 􀀀 ) symporter (NIS) is a plasma membrane glycoprotein with 13 transmembrane doma

FAQs

What is the main focus of this study on GSK5182?

The study focuses on whether the inverse agonist GSK5182 enhances the Na+/I− symporter (NIS) function in RAI-refractory papillary thyroid cancer cells.

How was radioiodine avidity assessed in the experiments?

RAI-refractory BCPAP cells were treated with GSK5182 for 24 h, and radioiodine avidity was determined with or without potassium perchlorate as an NIS inhibitor.

What mechanistic pathway is implicated for the GSK5182 effect on NIS function?

The work indicates involvement of ERRα modulation and the MAP kinase pathway, since MEK inhibition with U0126 reversed the increased radioiodine avidity induced by GSK5182.

Sep 24, 2026

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