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Specific inhibition of the activity of the urokinase receptor-mediated cell-surface plasminogen activation system by suramin.

ABSTRACT: 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.

SUBMITTER: Ellis V

PROVIDER: S-EPMC1137723 | biostudies-other | 1993 Dec

REPOSITORIES: biostudies-other

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Project description:Data from clinical studies, cell culture, and animal models implicate the urokinase (uPA)/Plasminogen (Plg) system in the development of atherosclerosis and aneurysms. However, the mechanisms through which uPA/Plg stimulate these diseases are not yet defined. We used genetically modified, atherosclerosis-prone mice, including mice with macrophage-specific uPA overexpression to clarify mechanisms of uPA/Plg-accelerated atherosclerosis and aneurysm formation. Microarray studies were performed to identify potential mediators of uPA-accelerated atherosclerosis. These studies identified S100A8 and S100A9 mRNA as the most highly upregulated transcripts in uPA-overexpressing macrophages; upregulation of S100A9 protein in uPA-overexpressing macrophages was confirmed by Western blotting. S100A8/A9, which are atherogenic in mice and are expressed in human atherosclerotic plaques, are also upregulated in aortae of mice with uPA-overexpressing macrophages, and macrophage S100A9 mRNA is upregulated by exposure of wild-type macrophages to medium from uPA-overexpressing macrophages. Bioinformatics analysis of the microarray data suggest significant effects of uPA overexpression on cell migration and cell-matrix interactions. Our results confirm—in a second animal model—that macrophage-expressed uPA stimulates atherosclerosis and aortic dilation. They also implicate specific pathways in uPA/Plg-accelerated atherosclerosis and aneurysmal disease. Six independent biological replicate RNA samples were prepared from thioglycollate-elicited peritoneal macrophages from mice of two different genotypes: SR-uPA+/0 transgenic (overexpress uPA in macrophages) and nontransgenic, respectively), for a total of 12 independent RNA samples. Both transgenic and nontransgenic mice were Apoe-/- and were fed Western diet from 5-15 weeks before peritoneal macrophages were elicited. In addition, from the six samples of each genotype, a pooled sample was prepared by combining the six genotype-specific samples. Each of the two pooled samples was assayed on the BeadChip in two technical replicates, for a total of 16 hybridizations performed using two Illumina Mouse Ref-8 v1.1 chips.

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Specific inhibition of the activity of the urokinase receptor-mediated cell-surface plasminogen activation system by suramin.

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