Ubenimex (bestatin) inhibits invasion and matrilysin activation of human uterine cervical adenocarcinoma OMC-4 cells

The purpose of the study was to investigate the effect of the aminopeptidase inhibitor ubenimex (bestatin) on the invasive activity of cultured human uterine cervical adenocarcinoma cells. The enzymatic degradation of the extracellular matrix by tumor cells during the invasive process was also examined. The invasion of cervical adenocarcinoma OMC-4 cells into reconstituted basement membrane (Matrigel) was inhi-bited by the presence of bestatin in a concentration-dependent manner. However, bestatin did not have any effect on tumor cell proliferation and migration. The casein zymography of tumor conditioned medium showed that the treatment of tumor cells with bestatin resulted in the drastic reduction of the 19 kDa-enzyme level (matrilysin, active form) and the slight reduction of the 28 kDa-enzyme level (matrilysin, latent form) in OMC-4 cells. The effect of bestatin on matrilysin secreted by OMC-4 cells were also confirmed by immunoblot analysis, and the disappearance of matrilysin in the active form was found. Bestatin inhibited hydrolysing activities towards substrates of aminopeptidases in tumor cells, but did not directly inhibit matrilysin. These results suggest that bestatin may inhibit the invasion of uterine cervical adenocarcinoma OMC-4 cells possibly through the inhibitory mechanisms for production and activation of matrilysin modulated by tumor aminopeptidases.