The effect of estrogen on the proliferation of endometrial cancer cells is mediated by ERRγ through AKT and ERK1/2

The objective of this study was to explore the effects and underlying mechanism of estrogen-related receptor gamma (ERR gamma) on the proliferation of endometrial carcinoma cells. Ishikawa cells, human endometrial cancer cells, were treated with estrogen. Immunofluorescence was used to observe the expression of ERR gamma. Stable transfection with the plasmid containing ERR gamma shRNA was carried out to knock down the expression of ERR gamma in Ishikawa cells. MTT assays were performed to analyze the proliferation of Ishikawa cells. The activation of extracellular signal-regulated protein kinase (ERK) 1/2 and activated protein kinase B (AKT) signaling pathways was identified using specific phosphorylated antibodies against ERK1/2 and AKT. PD98059, a MEK inhibitor, and LY294002, a PI3K inhibitor, were used in the inhibition experiments. ERR gamma could translocate from the cytoplasm to the nucleus in Ishikawa cells after exposure to estrogen. Knockdown of ERR gamma inhibited estrogen-induced proliferation of Ishikawa cells. More interestingly, knockdown of ERR gamma abolished the activation of ERK1/2 and AKT in the Ishikawa cells treated with estrogen. Inhibition of AKT in Ishikawa cells with LY294002 resulted in a significant reduction in the levels of phospho-ERK1/2, whereas inhibition of ERK1/2 with PD98059 exerted no effects on AKT activation. Our data showed that ERR gamma mediated the effects of estrogen on the proliferation of endometrial cancer cells through the activation AKT and ERK1/2 signaling pathways, which indicated that ERR gamma plays a key role in endometrial cancer. (c) 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.