Inverse Agonist of Estrogen-Related Receptor γ Enhances Sodium Iodide Symporter Function Through Mitogen-Activated Protein Kinase Signaling in Anaplastic Thyroid Cancer Cells.
Anaplastic thyroid cancer (ATC), a rare thyroid cancer with poor prognosis, is associated with insufficient function of the sodium iodide symporter (NIS). Estrogen-related receptor γ (ERRγ) is a member of the orphan nuclear receptors with important functions in cell development and homeostasis. However, there are no reports that demonstrate whether ERRγ is related to NIS function. Here, we evaluated the role of ERRγ in the regulation of NIS function in ATC cells using GSK5182, an inverse agonist of ERRγ.


METHODS
Two ATC cell lines, BHT-101 and CAL62, were incubated with GSK5182 at various time points and doses. The NIS function in the ATC cells was serially assessed by their uptake of radioiodine. The effects of GSK5182 on ERRγ and the mitogen-activated protein (MAP) kinase pathway, as well as on NIS protein, were evaluated by immunoblot assay. To examine whether the GSK5182-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, the MAP kinase activity and levels of radioiodine uptake were determined after application of a mitogen-activated protein kinase kinase (MEK) inhibitor to GSK5182-treated cells. Finally, the cytotoxic effect of (131)I was determined by clonogenic assay.


RESULTS
Treatment with GSK5182 resulted in dose- and time-dependent increases in iodide uptake in ATC cells, which were accompanied by both the downregulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK) 1/2. Both the increased radioiodine uptake and ERK1/2 activation of ATC cells were completely inhibited by the specific MEK inhibitor. GSK5182 treatment enhanced the membrane localization of NIS in both ATC cell lines. Accordingly, preexposure to GSK5182 enhanced the cytotoxic effects of (131)I treatment in ATC cells.


CONCLUSIONS
These findings suggest that the inverse agonist of ERRγ enhances the responsiveness of radioiodine therapy by modulating NIS function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway.
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.
Thoudam Debraj
TD
Singh
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.
Shin Young
SY
Jeong
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.
Sang-Woo
SW
Lee
Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Korea.
Jeoung-Hee
JH
Ha
Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.
In-Kyu
IK
Lee
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea; and.
Seong Heon
SH
Kim
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea; and.
Jina
J
Kim
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea; and.
Sung Jin
SJ
Cho
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.
Byeong-Cheol
BC
Ahn
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Korea New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea; and jeon9014@gmail.com jaetae@knu.ac.kr.
Jaetae
J
Lee
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Korea Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Korea jeon9014@gmail.com jaetae@knu.ac.kr.
Young Hyun
YH
Jeon
D015153:Blotting, Western; D045744:Cell Line, Tumor; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects*; D027981:Symporters / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D065646:Thyroid Carcinoma, Anaplastic / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D000099209:Sodium-Iodide Symporters
D020847:Estrogen Receptor Modulators; D007457:Iodine Radioisotopes; D020928:Mitogen-Activated Protein Kinases; D047428:Protein Kinase Inhibitors; D011960:Receptors, Estrogen; D027981:Symporters; D013629:Tamoxifen; D000099209:Sodium-Iodide Symporters; C583041:GSK5182; C425824:estrogen receptor gamma
MAP kinase signaling; anaplastic thyroid cancer; estrogen-related receptor gamma (ERRγ); radioiodide therapy; sodium iodide symporter (NIS)