Antitumor effect of XCT790, an ERRα inverse agonist, on ERα-negative endometrial cancer cells.

Purpose: The estrogen-related receptor (ERR) α is structurally similar to classical estrogen receptors (ERs), but is considered to be an orphan nuclear receptor. We previously found that ERRα regulates uterine endometrial cancer progression. Here, we investigated the efficacy of XCT790, a selective inverse agonist of ERRα, on endometrial cancer cells in vitro and in vivo.

Methods: HEC-1A and KLE, ERα-negative endometrial cancer cells exhibiting high ERRα expression levels, and HEC-1A cell-derived xenograft model mice were treated with XCT790. Transcriptional activity and cell proliferation were examined using luciferase, WST-8 and colony formation assays, respectively. Cell cycle progression was evaluated using flow cytometry, immunofluorescence cytochemistry and Western blotting. Apoptosis was evaluated using a caspase-3/7 activity assay.

Results: We found that XCT790 significantly inhibited ERRα-induced in vitro transcriptional activity, including that of the vascular endothelial growth factor (VEGF) gene, in a concentration-dependent manner (p < 0.05). We also found that XCT790 suppressed colony formation and cell proliferation in a concentration and time-dependent manner (p < 0.01) without cytotoxicity, and induced apoptosis (p < 0.01). XCT790 was found to cause cell cycle arrest at the mitotic phase. Akt and mTOR phosphorylation was found to be inhibited by XCT790, but PI3K levels were not found to be significantly affected. Combination therapy of XCT790 with paclitaxel elicited a synergistic inhibitory effect. Additionally, we found that XCT790 significantly inhibited in vivo tumor growth and angiogenesis, and induced apoptosis without a reduction in body weight, in xenograft models (p < 0.01).

Conclusions: From our data we conclude that XCT790 has an anti-tumor effect on endometrial cancer cells in vitro and in vivo. As such, it may serve as a novel therapeutic agent for endometrial cancer.