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Cellular Oncology

, Volume 42, Issue 2, pp 223–235 | Cite as

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

  • Tetsuya Kokabu
  • Taisuke MoriEmail author
  • Hiroshi Matsushima
  • Kaori Yoriki
  • Hisashi Kataoka
  • Yosuke Tarumi
  • Jo Kitawaki
Original Paper
  • 149 Downloads

Abstract

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.

Keywords

Uterine endometrial cancer Estrogen-related receptor XCT790 Apoptosis Cell cycle arrest 

Notes

Acknowledgments

The authors thank Maki Kawato, Ayumi Tanaka, Yunhwa Lee, and Ayaka Miura for technical assistance.

Funding

This study was supported in part by Grants-in-Aid for Scientific Research (15 K10726) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Compliance with ethical standards

Conflict of interest

The authors declare no competing financial interest.

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Copyright information

© International Society for Cellular Oncology 2019

Authors and Affiliations

  • Tetsuya Kokabu
    • 1
  • Taisuke Mori
    • 1
    Email author
  • Hiroshi Matsushima
    • 1
  • Kaori Yoriki
    • 1
  • Hisashi Kataoka
    • 1
  • Yosuke Tarumi
    • 1
  • Jo Kitawaki
    • 1
  1. 1.Department of Obstetrics and GynecologyKyoto Prefectural University of Medicine, Graduate School of Medical ScienceKyotoJapan

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