Abstract
1340
Objectives Previously, we have reported that inverse agonist of estrogen-related receptor gamma (ERRγ) enhance the NIS function through MAP kinase signaling in anaplastic thyroid cancer cells. These finding guarantee us to further investigate the effects of inverse agonist of ERRγ on NIS function in papillary thyroid cancer (PTC). Herein, we report the role of ERRγ on the regulation of NIS function in PTC cells using an inverse agonist of ERRγ, GSK5182.
Methods BCPAP cells were treated with various doses of GSK5182 for 24h, followed by iodide uptake to determine their NIS function with or without of KClO4 as a NIS inhibitor. The effects of GSK5182 on mitogen-activated protein (MAP) kinase pathway and NIS protein were evaluated by immunoblot assay. To check whether the MAP kinase pathway is crucial for the GSK5182-induced NIS functional activity, the MAP kinase activity and levels of iodide uptake were determined by the use of selective MEK inhibitors, including PD98059 and U0126. Finally, the cytotoxic effect of I-131 was determined by clonogenic assay.
Results Treatment of GSK5182 led to the dose-dependent increase of iodide uptake with its complete inhibition to basal level by co-incubation with KClO4, which were accompanied by the activation of extracellular signal-regulated kinase (ERK)-1/2. Both the increased iodide uptake and ERK-1/2 activation in GSK5182-treated BCPAP cells were completely inhibited by selective MEK inhibitors. Treatment of GSK5182 resulted in the marked increase of total and membrane NIS protein in BCPAP cells. The results of clonogenic assay with I-131 demonstrated that pre-exposure of GSK5182 led to enhanced cytotoxic effects of I-131, revealing that survival rates of GSK5182, I-131, and combination is 94.6 ± 11 %, 92.6 ±14% and 60.6 ±9 %, respectively.
Conclusions We successfully demonstrated that an inverse agonist of ERRγ, GSK5182, enhance the function of NIS protein via up-regulation of the MAP kinase signaling and consequently increase the responsiveness of radioiodine therapy in papillary thyroid cancer cells.