Oncotarget

Research Papers:

Metformin inhibits proliferation and growth hormone secretion of GH3 pituitary adenoma cells

Jiayin An, Xiangdong Pei, Zhenle Zang, Zheng Zhou, Jintao Hu, Xin Zheng, Yin Zhang, Jiaojiang He, Lian Duan, Rufei Shen, Weihua Zhang, Feng Zhu, Song Li and Hui Yang _

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Oncotarget. 2017; 8:37538-37549. https://doi.org/10.18632/oncotarget.16556

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Abstract

Jiayin An1,*, Xiangdong Pei1,*, Zhenle Zang1, Zheng Zhou1, Jintao Hu1, Xin Zheng1, Yin Zhang1, Jiaojiang He2, Lian Duan3, Rufei Shen3, Weihua Zhang4, Feng Zhu5, Song Li1 and Hui Yang1

1Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China

2Department of Neurosurgery, Lanzhou General Hospital of Chinese People’s Liberation Army, Lanzhou, China

3Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China

4Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA

5Innovative Drug Research Centre, University of Chongqing, Chongqing, China

*These authors have contributed equally to this work

Correspondence to:

Hui Yang, email: huiyangxinqiao@163.com

Song Li, email: dlisong3@163.com

Keywords: metformin, growth hormone-secreting pituitary adenoma, proliferation, ATF3, STAT3

Received: June 11, 2016    Accepted: February 06, 2017    Published: March 25, 2017

ABSTRACT

Metformin is an anti-hyperglycemic agent used to treat diabetes, and recent evidence suggests it has antitumor efficacy. Because growth hormone-secreting pituitary adenoma (GH-PA) patients have a high incidence of diabetes frequently treated with metformin, we assessed the antitumor effect of metformin on GH-PA. We found that metformin effectively inhibited proliferation and induced apoptosis in the GH-PA cell line GH3. We detected a decrease in mitochondrial membrane potential (MMP), an increase in expression of pro-apoptotic proteins, and a decrease in expression of an anti-apoptotic protein in metformin-treated GH3 cells, which suggests involvement of the mitochondrial-mediated apoptosis pathway. Inhibition of AMPK, which is activated by metformin, failed to reverse the antiproliferative effect. ATF3 was upregulated by metformin, and its knockdown significantly reduced metformin-induced apoptosis. In addition, GH secretion was inhibited by metformin through suppression of STAT3 activity independently of AMPK. Metformin also significantly suppressed cellular proliferation and GH secretion in primary human GH-PA cells. Metformin also significantly inhibited GH3 cell proliferation and GH secretion in vivo. ATF3 upregulation and p-STAT3 downregulation were confirmed in xenografts. These findings suggest metformin is a potentially promising therapeutic agent for the treatment of GH-PA, particularly in patients with diabetes.


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