title: Urokinase directly activates matrix metalloproteinases-9: a potential role in glioblastoma invasion.
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.
authors: Department of Pathology, University of Virginia, 415 Lane Road, MR5 Rm3332, Charlottesville, VA 22908, USA.
authors: Yunge
authors: Y
authors: Zhao
authors: Charles E
authors: CE
authors: Lyons
authors: Aizhen
authors: A
authors: Xiao
authors: Dennis J
authors: DJ
authors: Templeton
authors: Qingxiang Amy
authors: QA
authors: Sang
authors: Keith
authors: K
authors: Brew
authors: Isa M
authors: IM
authors: Hussaini
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation; D005353:Fibronectins / Q000737:chemistry; D005780:Gelatin / Q000737:chemistry; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000209:Acute-Phase Proteins; D005353:Fibronectins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D005780:Gelatin; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9