Ca2+ channel subunit α 1D promotes proliferation and migration of endometrial cancer cells mediated by 17β-estradiol via the G protein-coupled estrogen receptor

Calcium and calcium channels are closely related to the estrogen-induced nongenomic effect of endometrial carcinoma, but the specific role of calcium channels is unknown. This study aimed to explore the expression and the biologic effect of the L-type calcium channel in endometrial carcinoma cells and to clarify the molecular mechanism of the relationship between L-type calcium channels and estrogen. The immunohistochemical results showed that Ca2+ channel subunit alpha 1D (Cav1.3) expression was high in atypical hyperplasia (1.90 +/- 0.35) and endometrial carcinoma tissues (2.05 +/- 0.82) but weak (0.80 +/- 0.15) in benign endometrial tissues (P < 0.05). Treatment with 17 beta-estradiol rapidly increased Cav1.3 expression in a dose-and time-dependent manner, and 100 nM cell-impermeable beta-estradiol-6-(O-carboxymethyl) oxime: bovine serum albumin also promoted Cav1.3 expression. Transfection with small interfering RNA against G protein-coupled estrogen receptor (GPER) suppressed estrogen-induced up-regulation of Cav1.3 compared with control cells and markedly reduced the estrogen-induced phosphorylation of ERK1/2 and CREB. Knocking down the Cav1.3 significantly suppressed estrogen-stimulated Ca2+ influx, cell proliferation, and migration in endometrial cancer cells. Taken together, Cav1.3 was overexpressed in atypical hyperplasia and endometrial carcinoma, and the estrogen-induced phosphorylation of downstream molecular ERK1/2 and CREB is the result of activation of the GPER pathway. L-type channel Cav1.3 is required for estrogen-stimulated Ca2+ influx and contributes broadly to the development of endometrial cancer. The Cav1.3 channel may be a new target for endometrial carcinoma treatment.