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

// Jiayin An 1, * , Xiangdong Pei 1, * , Zhenle Zang 1 , Zheng Zhou 1 , Jintao Hu 1 , Xin Zheng 1 , Yin Zhang 1 , Jiaojiang He 2 , Lian Duan 3 , Rufei Shen 3 , Weihua Zhang 4 , Feng Zhu 5 , Song Li 1 and Hui Yang 1 1 Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China 2 Department of Neurosurgery, Lanzhou General Hospital of Chinese People’s Liberation Army, Lanzhou, China 3 Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China 4 Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA 5 Innovative 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.