Both u‐PA inhibition and vitronectin binding by plasminogen activator inhibitor 1 regulate HT1080 fibrosarcoma cell metastasis

Open Access
Publisher Website
Google Scholar
Abstract
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‐1VN−), plasminogen activator inhibition (PAI‐1INH−) or both (PAI‐1VN−,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‐1VN− compared with control virus‐infected cells. Migration of cells infected by virus expressing either PAI‐1INH− or PAI‐1VN−,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.