title: Urokinase induces proliferation of human ovarian cancer cells: characterization of structural elements required for growth factor function.
abstract: 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 [3H]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 cyclo19,31 uPA19-31 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.
authors.affiliation: Frauenklinik der Technischen Universität München, Klinikum rechts der Isar, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Fischer
authors.forename: V
authors.initials: V
authors.lastname: Lutz
authors.forename: O
authors.initials: O
authors.lastname: Wilhelm
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
authors.forename: H
authors.initials: H
authors.lastname: Graeff
authors.forename: P
authors.initials: P
authors.lastname: Heiss
authors.forename: T
authors.initials: T
authors.lastname: Nishiguchi
authors.forename: N
authors.initials: N
authors.lastname: Harbeck
authors.forename: H
authors.initials: H
authors.lastname: Kessler
authors.forename: T
authors.initials: T
authors.lastname: Luther
authors.forename: V
authors.initials: V
authors.lastname: Magdolen
authors.forename: U
authors.initials: U
authors.lastname: Reuning
mesh_terms: D000911:Antibodies, Monoclonal; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D016373:DNA, Antisense; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008214:Lymphocytes; D008970:Molecular Weight; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010960:Plasminogen Activators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D014162:Transfection; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D016373:DNA, Antisense; D004273:DNA, Neoplasm; C524898:PLAUR protein, human; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D010738:Type C Phospholipases; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator