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Urokinase directly activates matrix metalloproteinases-9: a potential role in glioblastoma invasion |
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| Authors: | Zhao Yunge Lyons Charles E Xiao Aizhen Templeton Dennis J Sang Qingxiang Amy Brew Keith Hussaini Isa M |
| Institution: | a Department of Pathology, University of Virginia, 415 Lane Road, MR5 Rm3332, Charlottesville, VA 22908, USA b Collaborative Mass Spectrometry Facility, University of Virginia, Charlottesville, VA 22908, USA c Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA d Department of Basic Biomedical Science, Florida Atlantic University, Boca Raton, FL 33431, USA |
| Abstract: | 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. |
| Keywords: | MMP-9 uPA Activation Cell invasion Glioblastoma Mass spectrum |
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