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

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, we re investigated in vitro, using a Transwell cell-culture chamber and Mere c ompared with specific protease inhibitors for MMPs, uPA and AP-N, respectiv ely, The invasion activity of PC-3 tells was effectively suppressed by zinc and by all protease inhibitors in a dose-dependent manner. The invasion ac tivity of LNCaP cells was almost unaffected by these inhibitors. In SKRC-1 cells, the invasion activity. was strongly suppressed by MP03, although a m oderate inhibition by zinc and bestatin was observed. The purified AP-N act ivity was strongly inhibited by zinc at a concentration similar to that sup pressing the invasion activity of PC-3 tells and this inhibition by zinc wa s apparently competitive. Although the purified uPA activity uPA was also i nhibited by zinc, this inhibition was uncompetitive. AP-N was expressed abu ndantly on the membrane fraction of PC-3 cells among these cells tested, wh ile 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 he inv olved in the invasion of human prostate cancer cells and that zinc probably participates in the invasion and metastasis of cancer cells through the re gulation of the enzymatic activity of AP-N and uPA in human cancerous prost ate.