The endocrine disruptor bisphenol A promotes nuclear ERRγ translocation, facilitating cell proliferation of Grade I endometrial cancer cells via EGF-dependent and EGF-independent pathways
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Endocrine disruptors have become a global social and public health problem since the late 1980s. Bisphenol A (BPA) has a steroid-like skeleton similar to estrogen and progesterone, and is an endocrine disruptor that disturbs the physiological hormone balance. The potential involvement of BPA in malignancy of endometrial cancer cells caused by overexposure of steroid hormones remains incompletely understood. The present study aimed at understanding the regulatory mechanism underlying BPA-induced cell proliferation in hormone-sensitive endometrial cancer cells. BPA selectively and significantly induced cell proliferation of Grade I endometrial cancer cells such as HEC265 and Ishikawa cells. In HEC265 and Ishikawa cells, BPA induced nuclear translocation of estrogen-related receptor γ (ERRγ) in a time-dependent manner and increased expression of BPA/ERRγ-target genes. In Ishikawa cells, BPA promoted the influx of Ca2+ followed by epidermal growth factor (EGF) secretion to the extracellular space. Furthermore, EGF secreted from Ishikawa had an autocrine effect, leading to activation of the EGFR/ERK pathway. Contrastingly, in HEC265 cells, BPA increased the expression of BPA/ERRγ-target genes but did not affect Ca2+ mobilization EGF secretion. In conclusion, BPA induced cell proliferation via the BPA/ERRγ/EGF/EGFR/ERK signaling pathway in Ishikawa cells and contrastingly, in HEC265 cells, induced cell proliferation through the BPA/ERRγ signaling pathway.
KeywordsBPA ERRγ EGF Cell proliferation Endometrial cancer cell
I would like to thank Yoichi Ueta, Yuuki Kamura, Misato Kawahara, Ryosuke Kawamura, Tatsuhiko Sugimoto, Erika Hatakeyama, Ayaka Hosoda, Jumpei Masuwa, Motonobu Mukai, Toshinori Mori, Kanae Ohashi, Saki Ohashi, Mami Ogawa, Suzuka Takahashi, Yui Teruya, Sayaka Fujita, Chisato Akiyama-Yamamuro, Mayu Kajioka, Manami Shiota, Yuri Sugano, Shihoko Sugino, Aoi Chiba, Kazuki Nobuhara, Yuki Matsubara, Syuto Miyake, Ryosuke Yamanaka, Yumi Matsuda, Misaki Mori, and Satoko Kodama for their contributions and helpful discussions. This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.
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Conflict of interest
The author declares no conflicts of interest in association with the present study.
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