Both u-PA inhibition and vitronectin binding by plasminogen activator inhibitor 1 regulate HT1080 fibrosarcoma cell metastasis.
Overexpression of plasminogen activator inhibitor 1 (PAI-1) reduces tumor cell migration in vitro and metastasis in mice in vivo by mechanisms involving either inhibition of urokinase plasminogen activator (u-PA) activity or competition for an integrin binding site on vitronectin. To analyze the effects of PAI-1 on tumor cell migration in vitro and metastasis in vivo, recombinant adenoviral vectors expressing wild-type or mutant PAI-1 proteins were constructed. The mutant PAI-1 proteins were defective in either vitronectin binding (PAI-1(VN-)), plasminogen activator inhibition (PAI-1(INH-)) or both (PAI-1(VN-,INH-)). In vitro, migration of HT1080 human fibrosarcoma cells through a reconstituted extracellular matrix (ECM) was reduced 73% by overexpression of wild-type PAI-1 and 65% by PAI-1(VN-) compared with control virus-infected cells. Migration of cells infected by virus expressing either PAI-1(INH-) or PAI-1(VN-,INH-) was unaffected, indicating a requirement for plasminogen activator inhibitory activity. In vivo, however, only overexpression of wild-type PAI-1 reduced the burden of metastasis by 68% compared with the control group. This indicates that both u-PA inhibition and PAI-1 ECM interactions contribute to the mechanism of PAI-1-mediated regulation of cell migration.
Praus
Michael
M
Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium.
Collen
Désiré
D
Gerard
Robert D
RD
D000818:Animals; D002465:Cell Movement; D005260:Female; D005354:Fibrosarcoma / Q000473:pathology* / Q000556:secondary*; D022761:Gene Transfer, Horizontal; D006801:Humans; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*; D019096:Vitronectin / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D019096:Vitronectin; D014568:Urokinase-Type Plasminogen Activator