Inhibition of aminopeptidase N (AP-N) and urokinase-type plasminogen activator (uPA) by zinc suppresses the invasion activity in human urological cancer cells

Abstract

Zinc is an essential heavy metal and is more abundant in human prostate and kidney than in other tissues. The effects of zinc on the invasion activity of human prostate and renal cancer cell lines, PC-3, LNCaP and SKRC-1, were investigated in vitro using a Transwell cell-culture chamber and were compared with specific protease inhibitors for MMPs, uPA and AP-N, respectively. The invasion activity of PC-3 cells was effectively suppressed by zinc and by all protease inhibitors in a dose-dependent manner. The invasion activity of LNCaP cells was almost unaffected by these inhibitors. In SKRC-1 cells, the invasion activity was strongly suppressed by MP03, although a moderate inhibition by zinc and bestatin was observed. The purified AP-N activity was strongly inhibited by zinc at a concentration similar to that suppressing the invasion activity of PC-3 cells and this inhibition by zinc was apparently competitive. Although the purified uPA activity was also inhibited by zinc, this inhibition was uncompetitive. AP-N was expressed abundantly on the membrane fraction of PC-3 cells among these cells tested, while its expression on the membrane fraction of SKRC-1 cells was weaker than that of PC-3 cells. The expression of uPA was also highest on the membrane fraction of PC-3 cells. These results suggest that AP-N and uPA may be involved in the invasion of human prostate cancer cells and that zinc probably participates in the invasion and metastasis of cancer cells through the regulation of the enzymatic activity of AP-N and uPA in human cancerous prostate.