Login to Access Video or Poster Abstract: MP17-16
Sources of Funding: NIH/R01 DK091353

Introduction

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 lower urinary symptoms, some of which may be related to bladder outlet obstruction. It is unclear whether anti-diabetic medications may prevent progression of lower urinary tract symptoms. We have previously found that stromally expressed insulin-like growth factor 1 (IGF-1) promotes benign prostatic epithelial (BPE) 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 BPE cells through reducing the expression of IGF-1 receptor (IGF-1R) and the adjustment of the cell cycle.

Methods

BPE cell lines (BPH-1 and P69) and a stromal cell line (3T3) 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-1 receptor was determined by western-blot and immunocytochemistry. The levels of IGF-1 secretion in a culture medium were 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 without inducing apoptosis. 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 BPE cells. Metformin (5mM) abrogated the proliferative effect of IGF-1 on BPE cells. In 3T3 cells, the secretion of IGF-1 was drastically inhibited by metformin from 574.31pg/ml to 197.61pg/ml. A conditioned medium of 3T3 cells promoted the proliferation and expression of IGF-1R in BPH-1 and P69 cells. Similarly, metformin abrogated the ability of a 3T3 conditioned medium to promote proliferation of BPE cells.

Conclusions

Our study demonstrates that metformin inhibits the proliferation of BPE cells by suppressing the expression of IGF-1R. Metformin may have a protective role in prostatic proliferation by inhibition of IGF-1R.

Funding

NIH/R01 DK091353