Oncotarget

Research Papers:

Metformin inhibits 17β-estradiol-induced epithelial-to-mesenchymal transition via βKlotho-related ERK1/2 signaling and AMPKα signaling in endometrial adenocarcinoma cells

Zhao Liu, Shasha Qi, Xingbo Zhao, Mingjiang Li, Sentai Ding, Jiaju Lu and Hui Zhang _

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Oncotarget. 2016; 7:21315-21331. https://doi.org/10.18632/oncotarget.7040

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Abstract

Zhao Liu1, Shasha Qi2, Xingbo Zhao2, Mingjiang Li2, Sentai Ding1, Jiaju Lu1 and Hui Zhang2

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.


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