Liu Hua, Zhang Liqin, Zhang Xuyan, Cui Zhumei
Department of Gynecology, Affiliated Hospital of Qingdao Medical College, Qingdao University, Qingdao.
Department of Gynecology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, People's Republic of China.
Onco Targets Ther. 2017 Jun 6;10:2865-2871. doi: 10.2147/OTT.S95267. eCollection 2017.
Endometrial cancer (EC) is now one of the most common malignant tumors in young women. In all, 90% of young patients with EC have a high expression of progesterone recep tor, can be treated with progestin, and have very good prognosis. However, some of the young EC patients are resistant to progestin, the mechanism of which is unclear. To illuminate the mechanism by which endometrial cells acquire progestin resistance, we treated Ishikawa cells by slowly increasing dosage of progestin and established a progestin-resistant cell subline. We show here that progesterone resistant cells acquire increased proliferation rate and interestingly decreased autophagy. To uncover the mechanism by which cells increase proliferation and bypass autophagy, we found higher activation of phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway was necessary to this malignant acquirement by RNAi technique. Further, we elucidated that activation of mTOR was sufficient and necessary for progestin resistance. RAD001, an inhibitor of mTOR, decreased phosphorylation of mTOR and inhibited proliferation of progestin-resistant cancer cells by promoting autophagy. Thus, our results indicated that mTOR can be a target to treat the progestin-resistant EC.
子宫内膜癌（EC）现已成为年轻女性中最常见的恶性肿瘤之一。总体而言，90%的年轻EC患者孕激素受体高表达，可采用孕激素治疗，且预后良好。然而，部分年轻EC患者对孕激素耐药，其机制尚不清楚。为阐明子宫内膜细胞获得孕激素耐药性的机制，我们通过逐步增加孕激素剂量处理 Ishikawa 细胞，建立了孕激素耐药细胞亚系。我们在此表明，孕激素耐药细胞的增殖速率增加，有趣的是自噬减少。为揭示细胞增殖增加并绕过自噬的机制，我们通过RNA干扰技术发现磷脂酰肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）信号通路的更高激活对于这种恶性获得是必要的。此外，我们阐明mTOR的激活对于孕激素耐药是充分且必要的。mTOR抑制剂RAD001通过促进自噬降低mTOR的磷酸化并抑制孕激素耐药癌细胞的增殖。因此，我们的结果表明mTOR可以作为治疗孕激素耐药性EC的靶点。
