Urokinase induces proliferation of human ovarian cancer cells: characterization of structural elements required for growth factor function

Ovarian cancer metastasis is associated with an increase in the urokinase-type plasminogen activator (uPA) and its receptor uPAR, We present evidence that binding of uPA to uPAR provokes a mitogenic response in the human ovarian cancer cell line OV-MZ-6 in which endogenous uPA production had been significantly reduced by stable uPA 'antisense' transfection, High molecular weight (HMW) uPA, independent of its enzymatic activity, produced an up to 95% increase in cell number concomitant with 2-fold elevated [(3)H]thymidine incorporation as did the catalytically inactive but uPAR binding amino-terminal fragment of uPA, ATF, uPA-induced cell proliferation was significantly decreased by blocking uPA/uPAR interaction by the monoclonal antibody IIIF10 and by soluble uPAR, The efficiency of the uPAR binding synthetic peptide cyclo(19,31)uPA(19-31) to enhance OV-MZ-6 cell growth proved this molecular domain to be the minimal structural determinant for uPA mitogenic activity. Dependence of uPA-provoked cell proliferation on uPAR was further demonstrated in Raji cells which do not express uPAR and were thus not induced by uPA, However, upon transfection with full-length uPAR, Raji cells acquired a significant growth response to HMW uPA and ATF, (C) 1998 Federation of European Biochemical Societies.