Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China.
Oncol Rep. 2018 Mar;39(3):1034-1042. doi: 10.3892/or.2017.6159. Epub 2017 Dec 15.
Gonadotropins, including luteinizing hormone (LH) and follicle stimulating hormone (FSH), are conducive to the growth of ovarian cancer based on the 'gonadotropin theory' and are regulated by gonadotropin-releasing hormone (GnRH). The present study was carried out to investigate the effect of goserelin, a GnRH agonist, on the apoptosis of epithelial ovarian cancer (EOC) cells and the underlying in vitro and in vivo mechanisms. Through flow cytometry, Hoechst staining and TUNEL staining, we demonstrated that goserelin promoted the apoptosis of EOC cells both in vitro and in vivo. Through human apoptosis gene PCR array, we verified that the promotion of EOC cell apoptosis by goserelin was linked to the upregulation of members of the tumor necrosis factor (TNF) and TNF receptor superfamilies, which have been identified as downstream targets of forkhead box O1 (FOXO1). Goserelin enhanced FOXO1 expression, and siRNA-mediated knockdown of FOXO1 abrogated the induction of apoptosis by goserelin. Moreover, goserelin decreased AKT activity, and FOXO1 upregulation by goserelin was dependent on the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In vivo, the expression of key factors in the PI3K/AKT/FOXO1 pathway was consistent with that observed in vitro. In conclusion, our data suggested that goserelin may promote EOC cell apoptosis by upregulating FOXO1 through the PI3K/AKT signaling pathway. We believe that GnRH agonists may be potential antitumor agents, and key factors in the PI3K/AKT-FOXO1 pathway may also be novel therapeutic targets for the treatment of EOC.
促性腺激素，包括黄体生成素（LH）和卵泡刺激素（FSH），基于“促性腺激素理论”有利于卵巢癌的生长，并受促性腺激素释放激素（GnRH）的调节。本研究旨在探讨 GnRH 激动剂戈舍瑞林对上皮性卵巢癌（EOC）细胞凋亡的影响及其体内外作用机制。通过流式细胞术、Hoechst 染色和 TUNEL 染色，我们证明戈舍瑞林在体内外均促进 EOC 细胞凋亡。通过人凋亡基因 PCR 阵列，我们验证了戈舍瑞林促进 EOC 细胞凋亡与肿瘤坏死因子（TNF）和 TNF 受体超家族成员的上调有关，这些成员已被确定为叉头框 O1（FOXO1）的下游靶标。戈舍瑞林增强 FOXO1 的表达，而 siRNA 介导的 FOXO1 敲低则消除了戈舍瑞林诱导的凋亡。此外，戈舍瑞林降低 AKT 活性，戈舍瑞林对 FOXO1 的上调依赖于磷脂酰肌醇 3-激酶（PI3K）/AKT 通路。在体内，PI3K/AKT/FOXO1 通路中的关键因子的表达与体外观察到的一致。总之，我们的数据表明，戈舍瑞林可能通过 PI3K/AKT 信号通路上调 FOXO1 促进 EOC 细胞凋亡。我们认为 GnRH 激动剂可能是潜在的抗肿瘤药物，PI3K/AKT-FOXO1 通路中的关键因素也可能是治疗 EOC 的新的治疗靶点。
