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Matrix metalloproteinase-9 (MMP-9) expression is known to enhance the invasion and metastasis of tumor cells. In previous work based on a proteomic screen, we identified the serpin protease nexin-1 (PN-1) as a potential target of MMP-9. Here, we show that PN-1 is a substrate for MMP-9 and establish a link between PN-1 degradation by MMP-9 and regulation of invasion. PN-1 levels increased in prostate carcinoma cells after downregulation of MMP-9 and in tissues of MMP-9-deficient mice, consistent with PN-1 degradation by MMP-9. We identified three MMP-9 cleavage sites in PN-1 and showed that mutations in those sites made PN-1 more resistant to MMP-9. Urokinase plasminogen activator (uPA) is inhibited by PN-1. MMP-9 augmented uPA activity in the medium of PC3-ML cells by degrading PN-1. Prostate cancer cells, overexpressing PN-1 or treated with MMP-9 shRNA, had reduced cell invasion in Matrigel. PN-1 siRNA restored uPA activity and the invasive 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.

Original publication

DOI

10.1158/0008-5472.CAN-10-0242

Type

Journal article

Journal

Cancer Res

Publication Date

01/09/2010

Volume

70

Pages

6988 - 6998

Keywords

Amyloid beta-Protein Precursor, Animals, Cell Line, Tumor, Humans, Male, Matrix Metalloproteinase 9, Mice, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Invasiveness, Prostatic Neoplasms, Protease Nexins, RNA, Small Interfering, Receptors, Cell Surface, Serpin E2, Serpins, Urokinase-Type Plasminogen Activator