PAI-1 mediates the antiangiogenic and profibrinolytic effects of 16K prolactin
- 15 June 2014
- journal article
- research article
- Published by Springer Nature in Nature Medicine
- Vol. 20 (7) , 741-747
Abstract
The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1-urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1-uPA-uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis.Keywords
This publication has 58 references indexed in Scilit:
- MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathyJournal of Clinical Investigation, 2013
- The Antiangiogenic 16K Prolactin Impairs Functional Tumor Neovascularization by Inhibiting Vessel MaturationPLOS ONE, 2011
- MicroRNA-21 Exhibits Antiangiogenic Function by Targeting RhoB Expression in Endothelial CellsPLOS ONE, 2011
- Factor XII stimulates ERK1/2 and Akt through uPAR, integrins, and the EGFR to initiate angiogenesisBlood, 2010
- Urokinase mediates endothelial cell survival via induction of the X-linked inhibitor of apoptosis proteinBlood, 2009
- Plasminogen Activator Inhibitor-1 Protects Endothelial Cells from FasL-Mediated ApoptosisCancer Cell, 2008
- Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapyProceedings of the National Academy of Sciences, 2006
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Plasminogen activator inhibitor 1. Structure of the native serpin, comparison to its other conformers and implications for serpin inactivationJournal of Molecular Biology, 2000
- Plasminogen activator inhibitor-1 gene-deficient mice. I. Generation by homologous recombination and characterization.Journal of Clinical Investigation, 1993