Phytoestrogen genistein inhibits EGFR/PI3K/NF-kB activation and induces apoptosis in human endometrial hyperplasial cells

Abstract

Endometrial hyperplasia is an estrogen-dependent disease and is the most frequent precursor of endometrial cancer, diagnosed in pre- and peri-menopausal women. Aside from estrogenic induction, peculiar activation of the epidermal growth factor receptor (EGFR) signal is well known to coordinate with endometrial hyperplasia and its related carcinoma and could be an important factor in aetiology of endometrial hyperplasia. Genistein is an abundant isoflavone in soy, and plays an important role in therapy of various diseases; however, the mechanism of action of genistein, towards endometrial hyperplasia is largely unknown. The current study was undertaken to explore the effect of genistein on cellular growth and the EGFR-mediated signaling pathway in endometrial hyperplasia. Results demonstrated that genistein significantly suppressed the growth of human endometrial hyperplasial cells through EGFR inhibition and its downstream effectors PI3K/Akt and NF-κB. Genistein induced apoptosis in human endometrial hyperplasial cells through intrinsic pathway. Genistein also decreased NF-κB nuclear accumulation which regulates cellular proliferation and p53-dependent apoptosis. In conclusion, genistein inhibits cell proliferation through discontinued EGFR signaling, and induces apoptosis in primary endometrial hyperplasial cells via inhibiting the cell survival pathway PI3K/Akt and NF-κB.