DN200434: An Inverse Agonist of Estrogen Related Receptor Gamma Enhances Na+/I- symporter Function through Mitogen-Activated Protein Kinase Signaling in Radioiodine-Refractory Papillary Thyroid Cancer Cells

Article

作者: Debraj Singh, Thoudam ; Gulwani, Deepak ; Sarangthem, Vijaya ; Upadhyay, Priyanka ; Goel, Ridhima

BACKGROUND:

Earlier, we have reported a series of inverse agonist of estrogen related receptor gamma (ERRγ), viz DN200434, GSK5182 and its derivates, that enhance sodium iodide (Na+/I-) symporter (NIS) function through mitogen-activated protein (MAP) kinase signaling in anaplastic thyroid cancer cells. But, the effect of our recently discovered DN200434, on NIS function in papillary thyroid cancer (PTC) refractory to radioactive iodine (RAI) therapy has not been reported. Herein, we studied the effects of DN200434 in RAI-resistant PTC cells on ERRγ-mediated regulation of NIS function.

METHODS:

RAI-refractory BCPAP cells were exposed to lower concentrations of DN200434 and the NIS function in the PTC cells was serially assessed by radioiodine uptake assay. Immunoblot assay was performed to study the effect of DN200434 on ERRγ, NIS, the mitogen-activated protein (MAP) kinase pathway, and iodide-handling genes. To examine whether the DN200434-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, radioiodine uptake was performed after the application of U0126, a selective MEK inhibitor to DN200434-treated cells. Finally, the cytotoxic effect of 131I was determined in DN200434 treated and untreated cells by clonogenic assay.

RESULTS:

Treatment of DN200434 resulted in dose-dependent increases in iodide uptake in BCPAP cells, downregulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK) 1/2. Treatment of the specific MEK inhibitor overturned the increased radioiodine uptake and ERK1/2 activation of BCPAP cells. DN200434 treatment enhanced the membrane localization of NIS in BCPAP cells. Clonogenic assay results revealed enhanced cytotoxic effects of 131I in DN200434 pre-exposed BCPAP cells.

CONCLUSION:

Thus, we successfully demonstrate that our novel inverse agonist of ERRγ, DN200434, enhances the responsiveness of radioiodine therapy by modulating NIS function in RAI-refractory papillary thyroid cancer cells via the regulation of ERRγ and the MAP kinase signaling pathway.

2025-09-01·BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS

Overcoming paclitaxel resistance in ovarian cancer cells using DN200434, an inverse agonist of estrogen-related receptor gamma (ERRγ)

Article

作者: Gulwani, Deepak ; Garg, Rachita ; Upadhyay, Priyanka ; Singh, Thoudam Debraj ; Goel, Ridhima

Ovarian cancer is one of the most prevalent gynecological malignancies in women. Resistance towards frontline chemotherapy, paclitaxel is a major obstacle in the management of cancer. This intricate phenomenon reduces the treatment efficacy, leading to poor patient prognosis. Recently, the nuclear receptor estrogen-related receptor γ (ERRγ) has been implicated in cancer progression and metastasis. In particular, the receptor is reported to be overexpressed in ovarian cancer, and its overexpression is associated with reduced overall survival. However, the effect of ERRγ targeting using the selective inverse agonist DN200434 on ovarian cancer progression remains to be explored. In this study, we report dose-dependent inhibition of SKOV-3 progression and parallel induction of apoptosis with DN2000434. Further, the potential of receptor targeting in sensitization towards taxol is shown in resistant SKOV-3 cells. The combination of DN200434 and paclitaxel induced resistance reversal via augmentation of cell cycle arrest and apoptosis. This phenomenon was corroborated in a 3-D agarose-based spheroid model.

2022-11-30·BMB reports

DN200434, an orally available inverse agonist of estrogen-related receptor γ, induces ferroptosis in sorafenib-resistant hepatocellular carcinoma

作者: Seunghyeong Lee ; Na-Young Kim ; Dong-Ho Kim ; Jae Won Yun ; Jun-Kyu Byun ; Jina Kim ; Jaebon Lee ; Sung Jin Cho ; Keun-Gyu Park ; In-Kyu Lee ; Yeon-Kyung Choi ; Jonghwa Jin ; Mi-Jin Kim ; Jungwook Chin

Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib. [BMB Reports 2022; 55(11): 547-552].

100 项与 DN-200434 相关的药物交易

登录后查看更多信息