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 urokin ase-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 pr oduction had been significantly reduced by stable uPA 'antisense' tran sfection, High molecular weight (HMW) uPA, independent of its enzymati c activity, produced an up to 95% increase in cell number concomitant with 2-fold elevated [H-3]thymidine incorporation as did the catalytic ally inactive but uPAR binding amino-terminal fragment of uPA, ATF, uP A-induced cell proliferation was significantly decreased by blocking u PA/uPAR interaction by the monoclonal antibody IIIF10 and by soluble u PAR, 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 demo nstrated in Raji cells which do not express uPAR and were thus not ind uced by uPA, However, upon transfection with full-length uPAR, Raji ce lls acquired a significant growth response to HMW uPA and ATF, (C) 199 8 Federation of European Biochemical Societies.