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

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

doi:10.18632/oncotarget.16556

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.

Highlights

growth hormone-secreting pituitary adenoma (GH-PA) is a common type of pituitary adenoma (PA)
Because patients with GHPA have a higher incidence of diabetes, which is the most well-known indication for the use of metformin, we explored the potential effects of metformin on the growth and GH secretion of GH-PAs in vitro using GH3 cell line, primary tumor cells and in vivo using nude mice
The expression of several mitochondrial apoptotic pathway-related proteins, including Bcl-2, Bax, and cleaved caspase-3(19), were determined by western blot analysis, which showed that the anti-apoptotic protein Bcl-2 was decreased by metformin in a dose-dependent manner

Summary

Introduction

GH-PA is a common type of pituitary adenoma (PA). Most GH-PAs are benign, they may cause patients to develop symptoms of acromegaly through hypersecretion of growth hormone (GH) [1]. The presence of excess GH and IGF-1 leads to a series of metabolic symptoms, including glucose intolerance (GI), diabetes mellitus (DM), hypertension, and several other endocrine disorders [2, 3]. If excess GH is sustained for a long period of time in vivo, the mortality rate may increase several fold, mainly due to cardiovascular complications [4, 5]. The treatments for GHPA include surgery, medical management, and radiotherapy. Some invasive GH-PAs exhibit poor responses to these approaches [6]. It is necessary to develop novel treatment strategies

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