Urokinase-type plasminogen activator (uPA) is involved in generating the proteolytic activity necessary for invasive processes, and is dependent on binding to its specific cellular receptor (uPAR) for efficient function. We report here that the polysulphonated napthylurea compound suramin inhibits the activity of this cell-associated proteolytic system, in a manner independent of its antagonism of the uPA-uPAR interaction [Behrendt, Rønne and Danø (1993) J. Biol. Chem. 268, 5985-5989], occurring at a 25-100-fold-lower suramin concentration. This inhibition was found to be due to effects on the activation of both pro-uPA and plasminogen. Suramin inhibited plasmin activation of pro-uPA by a non-competitive mechanism (Ki approx. 2 micrograms/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. The inhibition of plasminogen activation, which occurred exclusively with receptor-bound uPA, appeared to be due to a reversal of the favourable kinetics which result from the activation of cell-associated plasminogen, although suramin did not inhibit the cellular binding of 125I-labelled plasminogen. This suggests that this effect is due to interference with interactions between components of this system on the cell surface, and that suramin may be useful in gaining further insight into the molecular mechanisms involved in the functional assembly of this proteolytic system. Furthermore the effective inhibition of this system by suramin indicates an anti-invasive potential that may contribute to the anti-tumour effect of suramin in vivo.

This content is only available as a PDF.
You do not currently have access to this content.