A T-cell-related proteinase expressed by T-lymphoma cells activates their endogenous pro-urokinase.
In this report, we investigated the expression and activation of proteolytic enzymes by mouse T-lymphoma cell lines of differing metastatic potential. In contrast to the low metastatic Eb line, the metastatic variants ESb and ESb-MP secreted urokinase-type plasminogen activator (u-PA), which was present in the culture supernatant predominantly in the active form (ESb, 96%; ESb-MP, 80%). All three T-lymphoma variants expressed a mainly cell surface-associated proteinase, which proved to be immunologically and enzymatically related to the murine T-cell-associated serine proteinase-1 (MTSP-1). Intact lymphoma cells were able to activate the recombinant human proenzyme of u-PA (pro-u-PA) by a plasmin-independent mechanism, because plasmin contamination of the cells was not detectable. When ESb-MP cells were cultured in the presence of inhibitors of MTSP-1, such as antithrombin III, Pro-Phe-Arg-chloromethylketone, or aprotinin, the ratio of endogenously activated murine u-PA to inactive pro-u-PA in conditioned medium was significantly reduced (from 80% to 15%). The most potent inhibitor, antithrombin, did not inhibit plasmin-catalyzed pro-u-PA activation. These results suggest a novel autocrine mechanism of plasmin-independent pro-u-PA activation for metastatic T lymphomas by the production of an MTSP-1-related proteinase. The ability to initiate the proteolytic cascade of plasminogen activation in the absence of plasmin might contribute to the metastatic behavior of these cells observed in vivo.
Brunner
G
G
German Cancer Research Center, Institute of Immunology and Genetics, Heidelberg.
Vettel
U
U
Jobstmann
S
S
Kramer
M D
MD
Schirrmacher
V
V
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000990:Antithrombin III / Q000494:pharmacology; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007700:Kinetics; D016399:Lymphoma, T-Cell / Q000201:enzymology*; D051379:Mice; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000201:enzymology*; D014357:Trypsin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D000990:Antithrombin III; D010450:Endopeptidases; D014357:Trypsin; D014568:Urokinase-Type Plasminogen Activator