Pirfenidone inhibits motility of NSCLC cells by interfering with the urokinase system.

Pirfenidone inhibits motility of NSCLC cells by interfering with the urokinase system. Cell Signal. 2019 Nov 03;:109432 Authors: Krämer M, Markart P, Drakopanagiotakis F, Mamazhakypov A, Schaefer L, Didiasova M, Wygrecka M Abstract Pirfenidone (PFD) is an orally available synthetic drug which has been approved for the treatment of idiopathic pulmonary fibrosis. In addition to its anti-fibrotic properties, PFD also exerts anti-tumor effects in cancer models by inducing alterations in the tumor microenvironment. Here, we demonstrate that PFD reduces proliferation, 2D- and 3D-migration as well as colony formation of the non-small-cell lung carcinoma (NSCLC) cells. On a molecular level, we show that PFD on the one hand interacts with plasminogen activator inhibitor-1 (PAI-1; Kd of 46.2 ± 11.3 nM) and affects its inhibitory potency, but on the other hand it also increases PAI-1 expression; in both cases consequently leading to the reduction of urokinase (uPA) activity. Finally, we report that the effect of PFD on 2D-migration of NSCLC cells depends on PAI-1 expression and thus on the activity of the uPA system whereas the PFD-induced changes in cancer cell proliferation, 3D-migration and colony formation are PAI-1 independent. To conclude, a direct interference of PFD with the uPA-PAI-1 system may deregulate pericellular proteolytic activity and thereby influence the stability of the tumor blood vessels and the matrix architecture...
Source: Cellular Signalling - Category: Cytology Authors: Tags: Cell Signal Source Type: research