Urokinase directly activates matrix metalloproteinases-9: A potential role in glioblastoma invasion

• Published in: Biochemical and biophysical research communications Vol. 369; no. 4; pp. 1215 - 1220
• Main Authors: Zhao, Yunge, Lyons, Charles E., Xiao, Aizhen, Templeton, Dennis J., Sang, Qingxiang Amy, Brew, Keith, Hussaini, Isa M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.05.2008
• Subjects: Activation; Acute-Phase Proteins - metabolism; Brain Neoplasms - enzymology; Brain Neoplasms - pathology; Cell invasion; Enzyme Activation; Fibronectins - chemistry; Gelatin - chemistry; Glioblastoma; Glioblastoma - enzymology; Glioblastoma - pathology; Humans; Lipocalin-2; Lipocalins - metabolism; Mass spectrum; Matrix Metalloproteinase 9 - chemistry; Matrix Metalloproteinase 9 - metabolism; MMP-9; Neoplasm Invasiveness; Proto-Oncogene Proteins - metabolism; Tissue Inhibitor of Metalloproteinase-1 - metabolism; uPA; Urokinase-Type Plasminogen Activator - chemistry; Urokinase-Type Plasminogen Activator - metabolism; Mass spectrum; Activation; Cell invasion; MMP-9; uPA; Glioblastoma
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2008.03.038

Previous reports showed that urokinase plasminogen activator (uPA) converts plasminogen to plasmin which then activates matrix metalloproteinases (MMPs). Here, we report that uPA directly cleaved pro-MMP-9 in a time-dependent manner at both C- and N-terminus and generated two gelatinolytic bands. uPA-activated-MMP-9 efficiently degraded fibronectin and blocked by uPA inhibitor B428 and recombinant tissue inhibitor of metalloproteinase-1 (TIMP-1). B428 inhibited basal and PMA-induced active MMP-9 in glioblastomas (GBM) U1242 cell media as well as cell invasion in vitro. A combination of MMP-9 and uPA antibodies more significantly inhibited U1242 cell invasion than uPA or MMP-9 antibody alone. Both uPA and MMP-9 were highly expressed in U1242 cell and GBM patient specimens. Furthermore, two active MMP-9 fragments with identical molecular weights to the uPA-activated MMP-9 products were detected in GBM patient specimens. These results suggest that uPA-mediated direct activation of MMP-9 may promote GBM cell invasion.