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

FEBS Letters

Fischer, Kerstin²  Harbeck, Nadia²  Graeff, Henner²  Heiss, Peter⁵  Luther, Thomas¹  Kessler, Horst³  Schmitt, Manfred²  Wilhelm, Olaf²  Magdolen, Viktor²  Reuning, Ute²  Lutz, Verena²  Nishiguchi, Tomizo⁴ 

[1] Department of Pathology, Universität Dresden, Dresden, Germany;Frauenklinik der Technischen Universität München, Klinikum rechts der Isar, Ismaninger Str. 22, D-81675 Munich, Germany;Institut für Organische Chemie der Technischen Universität München, Munich, Germany;Hamamatsu University, School of Medicine, Hamamatsu, Japan;Department of Nuclear Medicine, Technische Universität München, Munich, Germany

关键词: Ovarian cancer;    Urokinase-type plasminogen activator;    Urokinase-type plasminogen activator receptor;    Mitogen;    Cell proliferation;    Antisense transfection;   

DOI  :  10.1016/S0014-5793(98)01279-4

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 cyclo^19,31uPA_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.

【 授权许可】

Unknown