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

Abstract

The objective of this study was to explore the effects and underlying mechanism of estrogen-related receptor γ (ERRγ) 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 ERRγ. Stable transfection with the plasmid containing ERRγ shRNA was carried out to knock down the expression of ERRγ 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. ERRγ could translocate from the cytoplasm to the nucleus in Ishikawa cells after exposure to estrogen. Knockdown of ERRγ inhibited estrogen-induced proliferation of Ishikawa cells. More interestingly, knockdown of ERRγ 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 ERRγ mediated the effects of estrogen on the proliferation of endometrial cancer cells through the activation AKT and ERK1/2 signaling pathways, which indicated that ERRγ plays a key role in endometrial cancer.