Abstract
Abstract G-protein coupled estrogen receptor 1 (GPER or GPR30) plays important roles in mediating estrogen action in many different tissues and organs under both physiological and pathological conditions. G-1 (1-[4-(6-bromobenzo[1,3]dioxol-5yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone), the putative selective GPER agonist, has been reported to activate GPER, trigger several signaling pathways, and stimulate cell proliferation in ER-negative breast cancer, endometrial and ovarian cancer. More recently, reports showed that activation of GPER by estrogen or G1 can suppress certain cell proliferation. This study was initiated to clarify the function of GPER and its agonist on the granulosa cell tumor (GCT) cell proliferation using KGN cell as a cellular model. Well characterized epithelial ovarian cancer and breast cancer cell lines were used for comparison. GPER siRNA was used to knock down GPER. Western blot and immunohistochemistry were used to detect protein expression. We found that knockdown of GPER significantly (P < 0.05) suppressed KGN cell proliferation, suggesting that GPER may play positive roles on KGN cell proliferation. Low concentrations of G1 (<500nM) had no effect on KGN cell proliferation, whereas higher concentrations (>1μM) of G1 significantly suppressed KGN cell proliferation and arrested KGN cells in G2/M phase. These results indicated that G1 may suppress KGN cell proliferation in a GPER-independent manner. Supporting our hypothesis, knockdown of GPER did not block the inhibitory effect of G1on KGN cell proliferation. Moreover, G15, a potent GPER antagonist, failed to block G1-induced suppression of cell proliferation and G1-induced cell cycle arrest in KGN cells. In IGROV-1 epithelial ovarian cancer cells, G1 suppressed cell proliferation, a response which was not blocked by G15, even at concentrations 8-fold higher than that of G1. G1 treatment also suppressed the proliferation of MDA-MB-231 breast cancer cells, a cell line which reportedly expresses very low amounts of GPER. In HEK-293 cells, which are reported to have no expression of GPER, G1 also significantly suppressed the cell proliferation and induced cell cycle arrest. In conclusion, our results demonstrate that G1 is able to suppress ovarian and breast cancer cell proliferation in a GPER-independent manner. G1 may be a candidate for the development of drugs against ovarian and breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3920. doi:1538-7445.AM2012-3920
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