SPECIFIC-INHIBITION OF THE ACTIVITY OF THE UROKINASE RECEPTOR-MEDIATED CELL-SURFACE PLASMINOGEN ACTIVATION SYSTEM BY SURAMIN

Urokinase-type plasminogen activator (uPA) is involved in generating t he proteolytic activity necessary for invasive processes, and is depen dent on binding to its specific cellular receptor (uPAR) for efficient function. We report here that the polysulphonated napthylurea compoun d suramin inhibits the activity of this cell-associated proteolytic sy stem, in a manner independent of its antagonism of the uPA-uPAR intera ction [Behrendt, Ronne and Dano (1993) J. Biol. Chem. 268, 5985-5989], occurring at a 25-100-fold-lower suramin concentration. This inhibiti on was found to be due to effects on the activation of both pro-uPA an d plasminogen. Suramin inhibited plasmin activation of pro-uPA by a no n-competitive mechanism (K(i) approx. 2 mug/ml), which did not involve a direct effect on plasmin catalytic activity. Similarly, its effect on plasminogen activation was not due to a direct inhibition of uPA. T he inhibition of plasminogen activation, which occurred exclusively wi th receptor-bound uPA, appeared to be due to a reversal of the favoura ble kinetics which result from the activation of cell-associated plasm inogen, although suramin did not inhibit the cellular binding of I-125 -labelled plasminogen. This suggests that this effect is due to interf erence with interactions between components of this system on the cell surface, and that suramin may be useful in gaining further insight in to the molecular mechanisms involved in the functional assembly of thi s proteolytic system. Furthermore the effective inhibition of this sys tem by suramin indicates an anti-invasive potential that may contribut e to the anti-tumour effect of suramin in vivo.