Beschreibung:
Abstract Plasminogen-activator inhibitor-1 (PAI-1) is a member of the serine protease (serpin) family of inhibitors that control the proteolytic activity of urokinase and tissue-type PA. The expression of PAI-1 in most cancer types has been shown to be a marker of poor rather than favorable outcome, suggesting that PAI-1 has a pro-tumorigenic activity. The observation that PAI-1 positively contributes to angiogenesis has in part provided a mechanism in support of the pro-tumorigenic effect of PAI-1. Consistent with such a role, we have previously reported that PAI-1 protects endothelial cells (EC) from FasL-mediated apoptosis by controlling FasL cleavage by plasmin (Bajou et al, Cancer Cell, 2008). Here we hypothesized that PAI-1 may play a similar protective role in cancer cells by preventing them from undergoing apoptosis. We observed that downregulation of PAI-1 by small interfering RNA (siRNA) induces apoptosis in breast cancer MDA-MB-231 cells (14.1 ±1.1% apoptotic cells in PAI-1 siRNA-treated cells vs. 1.5 ± 0.5% apoptotic cells in scramble control; p < 0.001) and increases caspase-3 activity by 5 fold. Consistent with an involvement of the extrinsic apoptotic pathway, we observed that downregulation of PAI-1 in MDA-MB-231 cells did not alter mitochondrial membrane potential but resulted in an increase in caspase-8 activity by 3 fold. PAI-1 silencing also enhanced the production of urokinase (uPA) and the cell-associated activity of plasmin, and inhibited migration and invasion in vitro. The data thus suggest that like in EC, PAI-1 protects tumor cells from extrinsic apoptosis and provides an additional mechanism explaining the pro-tumorigenic activity of PAI-1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 518.