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 [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.
Fischer
K
K
Frauenklinik der Technischen Universität München, Klinikum rechts der Isar, Munich, Germany.
Lutz
V
V
Wilhelm
O
O
Schmitt
M
M
Graeff
H
H
Heiss
P
P
Nishiguchi
T
T
Harbeck
N
N
Kessler
H
H
Luther
T
T
Magdolen
V
V
Reuning
U
U
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*
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