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Urokinase induces proliferation of human ovarian cancer cells: characterization of structural elements required for growth factor function
Author(s) -
Fischer Kerstin,
Lutz Verena,
Wilhelm Olaf,
Schmitt Manfred,
Graeff Henner,
Heiss Peter,
Nishiguchi Tomizo,
Harbeck Nadia,
Kessler Horst,
Luther Thomas,
Magdolen Viktor,
Reuning Ute
Publication year - 1998
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(98)01279-4
Subject(s) - urokinase receptor , transfection , cell growth , chemistry , cancer research , cell culture , microbiology and biotechnology , urokinase , plasminogen activator , cancer cell , receptor , biology , biochemistry , cancer , endocrinology , genetics
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.