title: Metformin inhibits the proliferation of benign prostatic epithelial cells.
abstract: OBJECTIVE
  Benign prostatic hyperplasia (BPH) is the most common proliferative abnormality of the prostate affecting elderly men throughout the world. Epidemiologic studies have shown that diabetes significantly increases the risk of developing BPH, although whether anti-diabetic medications preventing the development of BPH remains to be defined. We have previously found that stromally expressed insulin-like growth factor 1 (IGF-1) promotes benign prostatic epithelial cell proliferation through paracrine mechanisms. Here, we seek to understand if metformin, a first line medication for the treatment of type 2 diabetes, inhibits the proliferation of benign prostatic epithelial cells through reducing the expression of IGF-1 receptor (IGF-1R) and regulating cell cycle.
  
  
  METHODS
  BPE cell lines BPH-1 and P69, murine fibroblasts3T3 and primary human prostatic fibroblasts were cultured and tested in this study. Cell proliferation and the cell cycle were analyzed by MTS assay and flow cytometry, respectively. The expression of IGF-1R was determined by western-blot and immunocytochemistry. The level of IGF-1 secretion in culture medium was measured by ELISA.
  
  
  RESULTS
  Metformin (0.5-10mM, 6-48h) significantly inhibited the proliferation of BPH-1 and P69 cells in a dose-dependent and time-dependent manner. Treatment with metformin for 24 hours lowered the G2/M cell population by 43.24% in P69 cells and 24.22% in BPH-1 cells. On the other hand, IGF-1 (100ng/mL, 24h) stimulated the cell proliferation (increased by 28.81% in P69 cells and 20.95% in BPH-1 cells) and significantly enhanced the expression of IGF-1R in benign prostatic epithelial cells. Metformin (5mM) abrogated the proliferation of benign prostatic epithelial cells induced by IGF-1. In 3T3 cells, the secretion of IGF-1 was significantly inhibited by metformin from 574.31pg/ml to 197.61pg/ml. The conditioned media of 3T3 cells and human prostatic fibroblasts promoted the proliferation of epithelial cells and the expression of IGF-1R in epithelial cells. Metformin abrogated the proliferation of benign prostatic epithelial cells promoted by 3T3 conditioned medium.
  
  
  CONCLUSIONS
  Our study demonstrates that metformin inhibits the proliferation of benign prostatic epithelial cells by suppressing the expression of IGF-1R and IGF-1 secretion in stromal cells. Metformin lowers the G2/M cell population and simultaneously increases the G0/G1 population. Findings here might have significant clinical implications in management of BPH patients treated with metformin.
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Department of Urology, Wuhan Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xingyuan
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Rongbin
authors.initials: R
authors.lastname: Ge
authors.affiliation: Shanghai Children 's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jijun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Johnson
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Rassoulian
authors.affiliation: Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Aria F
authors.initials: AF
authors.lastname: Olumi
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects*; D056741:Cyclin D / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology / Q000187:drug effects*; D011470:Prostatic Hyperplasia / Q000473:pathology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D056741:Cyclin D; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D017526:Receptor, IGF Type 1