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Title: $Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition <i>via</i> βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells
Abstract: // Zhao Liu 1 , Shasha Qi 2 , Xingbo Zhao 2 , Mingjiang Li 2 , Sentai Ding 1 , Jiaju Lu 1 and Hui Zhang 2 1 Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China 2 Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People's Republic of China Correspondence to: Hui Zhang, email: // Keywords : metformin, βKlotho, 17β-estradiol, epithelial-mesenchymal transition, endometrial adenocarcinoma Received : August 14, 2015 Accepted : January 19, 2016 Published : January 27, 2016 Abstract 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.