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

Cells. 2023 Feb 1;12(3):470. doi: 10.3390/cells12030470.

Abstract

Previously, we reported that an inverse agonist of estrogen-related receptor gamma (ERRγ), 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 ERRγ 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 (KClO4) as an NIS inhibitor. We explored the effects of GSK5182 on ERRγ, 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 KClO4 in BCPAP cells. We found that ERRγ 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 ERRγ, GSK5182, enhances the function of NIS protein via the modulation of ERRγ and MAP kinase signaling, thereby leading to increased responsiveness to radioiodine in RAI-refractory papillary thyroid cancer cells.

Keywords: estrogen-related receptor gamma; radioiodine therapy; radioiodine uptake; radioiodine-refractory papillary thyroid cancer cells; sodium iodide symporter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Inverse Agonism
  • Estrogens
  • Humans
  • Iodides / metabolism
  • Iodine Radioisotopes / therapeutic use
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogens
  • Symporters* / genetics
  • Symporters* / metabolism
  • Thyroid Cancer, Papillary / drug therapy
  • Thyroid Cancer, Papillary / radiotherapy
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / metabolism
  • Thyroid Neoplasms* / radiotherapy

Substances

  • Iodine-131
  • Iodine Radioisotopes
  • GSK5182
  • sodium-iodide symporter
  • Iodides
  • Mitogens
  • Symporters
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Estrogens

Grants and funding

This work was supported by the Science & Engineering Research Board (SERB), India, (Sanction order no. CRG/2019/000361), Department of Health Research (DHR), India (File No.R.11012/06/2021-GIA/HR), Intramural Research Grant (2017–2019) from All India Institute of Medical Sciences, New Delhi, by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2022R1A2C1004096, NRF-2021R1C1C1009833, NRF-2021R1A4A1025662), by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), by the National Research Foundation of Korea (NRF) grant funded by the Korean government (2021R1A5A2021614), and by the Ministry of Health & Welfare, Republic of Korea (grant number: HI22C1988).