URINARY TRYPSIN-INHIBITOR (UTI) AND FRAGMENTS DERIVED FROM UTI BY LIMITED PROTEOLYSIS EFFICIENTLY INHIBIT TUMOR-CELL INVASION

We investigated the effects of purified human urinary trypsin inhibito r (UTI) and fragments derived from UTI by proteolysis on the invasive potential of ovarian cancer cells (HOC-I) and gestational choriocarcin oma cells (SMT-ccl) using an in vitro reconstituted basement membrane invasion assay. These cells express cell-associated plasmin and functi onal uPA receptors that are partially occupied by ligands. SMT-ccl cel ls, which express threefold higher levels of cell-associated plasmin a ctivity than HOC-I cells, showed approximately twofold increase in the ir invasive potential. For the invasion assay, HOC-I celts were primed with exogenous plasminogen, but SMT-ccl cells were not. Human leukocy te elastase (HLE)-digested UTI (22 kDa fragment; UTI-22) inhibited pla smin practically with the same strength as native UTI. Trypsin-digeste d UTI (20 kDa fragment; UTI-20), however, did not inhibit plasmin sign ificantly. Treatment of cells with UTI or UTI-22 reduced the incidence of tumor cell invasive capacity, whereas the inhibitory effect of UTI -20 was not remarkable. The inhibitory effect on tumor cell invasion w as dose-dependent and non-toxic; moreover, it was not mediated by inhi bition of the tumor cell chemotactic response or of cell attachment to matrigel. These results indicate that inhibition of the proteolytic e nzyme plasmin specifically reduced the invasive capacity of tumor cell s in vitro.