Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

Abstract

This study was performed to evaluate the anticancer effects of tolerable doses of metformin with or without medroxyprogesterone (MPA) in endometrial cancer cells. Cell viability, cell invasion, and levels of matrix metallopeptidase (MMP) and transforming growth factor (TGF)-{beta}1 were analyzed using three human endometrial adenocarcinoma cell lines (Ishikawa, KLE, and USPC) after treatment with different dose combinations of MPA (0, 10 M) and metformin (0, 100, 1000 M). Combining metformin (0, 100, 1000 M) and 10 M MPA induced significantly decreased cell viability in a time- and dose-dependent manner in Ishikawa cells, but not in KLE and USPC cells. There was no dose- or time-dependent cell growth inhibition, or positive western blot results for the expression of progesterone receptors and phospho-AMPKa, following treatment with any combination of metformin (0, 100, 1000 M) and 10 M MPA in KLE and USPC cells. In KLE cells, metformin treatment alone significantly inhibited cell invasion in a dose-dependent manner (1.31{+/-}0.05, 0.94{+/-}0.04, 0.83{+/-}0.05 at 0, 100 M, 1000 M, respectively; p<0.0005). The inhibitory effect of metformin was reversed to create a stimulating effect when metformin was combined with 10 M MPA (1.10{+/-}0.05, 1.42{+/-}0.18, 1.41{+/-}0.26 at 0, 100, 1000 M, respectively; p<0.005). MMP-9 and TGF-{beta}1 showed similar trends in terms of cell invasion in KLE cells. In conclusion, the anti-invasive effect of metformin in KLE cells was completely reversed to the state of no treatment by the addition of MPA; this might be mediated through MMP-9 and TGF-{beta}1. Our study suggests the possibility of these combinations doing harm, rather than good, under some conditions.