Tum Mat Inva

Downlo rix metalloproteinase-9 (MMP-9) expression is known to enhance the invasion and metastasis of tumor n previous work based on a proteomic screen, we identified the serpin protease nexin-1 (PN-1) as a ial target of MMP-9. Here, we show that PN-1 is a substrate for MMP-9 and establish a link between egradation by MMP-9 and regulation of invasion. PN-1 levels increased in prostate carcinoma cells after egulation of MMP-9 and in tissues of MMP-9–deficient mice, consistent with PN-1 degradation by 9. We identified three MMP-9 cleavage sites in PN-1 and showed that mutations in those sites made ore resistant to MMP-9. Urokinase plasminogen activator (uPA) is inhibited by PN-1. MMP-9 augmentactivity in the medium of PC3-ML cells by degrading PN-1. Prostate cancer cells, overexpressing PN-1 ted with MMP-9 shRNA, had reduced cell invasion in Matrigel. PN-1 siRNA restored uPA activity and vasive capacity. PN-1 mutated in the serpin inhibitory domain, the reactive center loop, failed to inhibit uPA and to reduce Matrigel invasion. This study shows a novel molecular pathway in which MMP-9 regulates uPA activity and tumor cell invasion through cleavage of PN-1. Cancer Res; 70(17); 6988–98. ©2010 AACR.