Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, No 324 Jingwu Road, Jinan, 250021, Shandong, China.
Department of Obstetrics and Gynecology, Provincial Hospital Affiliated to Shandong University, No 324 Jingwu Road, Jinan, 250021, Shandong, China.
Eur J Pharmacol. 2019 Sep 15;859:172541. doi: 10.1016/j.ejphar.2019.172541. Epub 2019 Jul 15.
Endometrial cancer is the most common cancer of the female reproductive system in the developed countries. Metformin is a widely used medication that has been prescribed to treat type 2 diabetes. In recent years, metformin has been found to improve the survival prognosis of cancer patients clinically. We aimed to investigate inhibition of metformin on the proliferation of endometrial carcinoma. Metformin was used to treat endometrial cancer cell lines Ishikawa and RL95-2. The expression of programmed death-ligand 1 (PD-L1) in the treated cells was assessed by western blot. The tumor cell proliferation was evaluated by colony formation assay. The binding between PD-L1 and AMP-activated protein kinase (AMPK) was identified by co-immunoprecipitation. Ishikawa and RL95-2 cells were co-cultured with activated T cells to detect the survival of Ishikawa and RL95-2 cells in the presence or absence of metformin. Our results showed that metformin treatment on endometrial cancer cells Ishikawa and RL95-2 decreased the expression level of PD-L1 protein. Metformin treatment significantly activated T cells against Ishikawa and RL95-2 cells. We demonstrated that the inhibition of PD-L1 by metformin is dependent on the AMPK signaling protein, and that metformin promotes direct binding of the AMPK protein to the PD-L1 protein. We confirmed that metformin, a conventional medication used in diabetes therapy, holds anti-tumor activity in endometrial cancer. The suppression of metformin is relevant to the inhibition of PD-L1 expression and the activation of AMPK signaling protein, providing a novel mechanism in the anti-tumor property of metformin.
子宫内膜癌是发达国家女性生殖系统最常见的癌症。二甲双胍是一种广泛应用于治疗 2 型糖尿病的药物。近年来，二甲双胍被发现能改善癌症患者的临床生存预后。我们旨在研究二甲双胍对子宫内膜癌增殖的抑制作用。用二甲双胍治疗子宫内膜癌细胞系 Ishikawa 和 RL95-2。通过 Western blot 评估处理细胞中程序性死亡配体 1（PD-L1）的表达。通过集落形成实验评估肿瘤细胞增殖。通过共免疫沉淀鉴定 PD-L1 与 AMP 激活蛋白激酶（AMPK）之间的结合。将 Ishikawa 和 RL95-2 细胞与激活的 T 细胞共培养，以检测在存在或不存在二甲双胍的情况下 Ishikawa 和 RL95-2 细胞的存活情况。我们的结果表明，二甲双胍处理子宫内膜癌细胞系 Ishikawa 和 RL95-2 可降低 PD-L1 蛋白的表达水平。二甲双胍处理可显著激活 T 细胞对 Ishikawa 和 RL95-2 细胞的杀伤作用。我们证明，二甲双胍对 PD-L1 的抑制作用依赖于 AMPK 信号蛋白，并且二甲双胍促进 AMPK 蛋白与 PD-L1 蛋白的直接结合。我们证实，二甲双胍作为糖尿病治疗中的常规药物，在子宫内膜癌中具有抗肿瘤活性。二甲双胍的抑制作用与 PD-L1 表达的抑制和 AMPK 信号蛋白的激活有关，为二甲双胍的抗肿瘤特性提供了一种新的机制。
