Liu Zhao, Qi Shasha, Zhao Xingbo, Li Mingjiang, Ding Sentai, Lu Jiaju, Zhang Hui
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China.
Oncotarget. 2016 Apr 19;7(16):21315-31. doi: 10.18632/oncotarget.7040.
The potential role of metformin in treating endometrial cancer remains to be explored. The current study investigated the role of metformin in 17β-estradiol-induced epithelial-mesenchymal transition (EMT) in endometrial adenocarcinoma cells. We found that 17β-estradiol promoted proliferation and migration, attenuated apoptosis in both estrogen receptor (ER) positive and ER negative endometrial adenocarcinoma cells (Ishikawa and KLE cells, respectively). Metformin abolished 17β-estradiol-induced cell proliferation and reversed 17β-estradiol-induced EMT in Ishikawa cells. In addition, metformin increased the expression of βKlotho, a fibroblast growth factors (FGFs) coreceptor, and decreased ERK1/2 phosphorylation in both Ishikawa and KLE cells. Decreased expression of βKlotho was noted in human endometrial adenocarcinomas, and plasmid-driven expression of βKlotho in Ishikawa cells abolished 17β-estradiol-induced EMT via inhibiting ERK1/2 signaling. βKlotho expression and metformin show synergetic effects on the proliferation and the EMT in Ishikawa cells. Furthermore, we demonstrated that the anti-EMT effects of metformin could be partly abolished by introducing Compound C, a specific AMPKα signaling inhibitor. In conclusion, metformin abolishes 17β-estradiol-induced cell proliferation and EMT in endometrial adenocarcinoma cells by upregulating βKlotho expression, inhibiting ERK1/2 signaling, and activating AMPKα signaling. Our study provides novel mechanistic insight into the anti-tumor effects of metformin.
二甲双胍在治疗子宫内膜癌中的潜在作用仍有待探索。本研究调查了二甲双胍在17β-雌二醇诱导的子宫内膜腺癌细胞上皮-间质转化（EMT）中的作用。我们发现，17β-雌二醇促进了雌激素受体（ER）阳性和ER阴性子宫内膜腺癌细胞（分别为Ishikawa细胞和KLE细胞）的增殖和迁移，并减弱了细胞凋亡。二甲双胍消除了17β-雌二醇诱导的Ishikawa细胞增殖，并逆转了17β-雌二醇诱导的EMT。此外，二甲双胍增加了成纤维细胞生长因子（FGFs）共受体βKlotho的表达，并降低了Ishikawa细胞和KLE细胞中ERK1/2的磷酸化水平。在人子宫内膜腺癌中发现βKlotho的表达降低，而Ishikawa细胞中质粒驱动的βKlotho表达通过抑制ERK1/2信号通路消除了17β-雌二醇诱导的EMT。βKlotho表达和二甲双胍对Ishikawa细胞的增殖和EMT具有协同作用。此外，我们证明，引入特异性AMPKα信号抑制剂Compound C可部分消除二甲双胍的抗EMT作用。总之，二甲双胍通过上调βKlotho表达、抑制ERK1/2信号通路和激活AMPKα信号通路，消除了17β-雌二醇诱导的子宫内膜腺癌细胞增殖和EMT。我们的研究为二甲双胍的抗肿瘤作用提供了新的机制见解。
