期刊
CELLULAR SIGNALLING
卷 65, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2019.109432
关键词
Non-small-cell lung carcinoma; Urokinase; Plasminogen activator inhibitor-1; Pirfenidone
类别
资金
- German Research Foundation [DFG: WY119/1-3, SFB 815, SFB 1039, SFB 1177, SCHA 1082/6-1]
- Cardio-Pulmonary Institute (CPI) [EXC 2026, 390649896]
- LUNGENF-IBR02P(R)e.V. Foundation
- German Center for Lung Research
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; K-d 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 within tumor stroma.
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