Expression of active plasminogen activator inhibitor-1 reduces cell migration and invasion in breast and gynecological cancer cells.
Urokinase-type (uPA) plasminogen activator is regulated by serine protease inhibitors (serpins), especially plasminogen activator inhibitor-1 (PAI-1). In many cancers, uPA and PAI-1 contribute to the invasive phenotype. We examined the in vitro migration and invasive capabilities of breast, ovarian, endometrial, and cervical cancer cell lines compared to their plasminogen activator system profiles. We then overexpressed active wild-type PAI-1 and an inactive "substrate" P14 form of PAI-1 (T333R) using stable transfection and adenoviral gene delivery. We also upregulated endogenous uPA and PAI-1 in these cells by treatment with transforming growth factor-beta. Some breast and ovarian cancer cell lines with natural expression of uPA, PAI-1, and urokinase receptor showed substantial migration and invasion compared to other cell lines that lack expression of these proteins. However, overexpression of active wild-type PAI-1, but not P14-PAI-1 (T333R), in these cell lines showed reduced migration and invasion. Since vitronectin binding by both forms of PAI-1 is equivalent, these results imply that PAI-1-vitronectin interactions are less critical in altering migration and invasion. Our results show that the in vitro migratory and invasive phenotype in these breast and ovarian cancer cell lines is reduced by active PAI-1 due to its ability to inhibit plasminogen activation.
Whitley
Brandi R
BR
Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7035, USA.
Palmieri
Diane
D
Twerdi
Christine D
CD
Church
Frank C
FC
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D005833:Genital Neoplasms, Female / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D019096:Vitronectin / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D019096:Vitronectin; D014568:Urokinase-Type Plasminogen Activator