title: Metformin inhibits proliferation and growth hormone secretion of GH3 pituitary adenoma cells.
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.
authors.affiliation: Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jiayin
authors.initials: J
authors.lastname: An
authors.affiliation: Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Pei
authors.affiliation: Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zhenle
authors.initials: Z
authors.lastname: Zang
authors.affiliation: Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jintao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Lanzhou General Hospital of Chinese People's Liberation Army, Lanzhou, China.
authors.forename: Jiaojiang
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Duan
authors.affiliation: Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Rufei
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Biology and Biochemistry, College of Natural Sciences and Mathematics, University of Houston, Houston, Texas, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Innovative Drug Research Centre, University of Chongqing, Chongqing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Multidisciplinary Center for Pituitary Adenomas of Chongqing, Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000236:Adenoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D051700:Activating Transcription Factor 3; D007004:Hypoglycemic Agents; D013006:Growth Hormone; D008687:Metformin
keywords: ATF3; STAT3; growth hormone-secreting pituitary adenoma; metformin; proliferation