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Angiogenesis, Metastasis, and the Cellular Microenvironment

Activation of Peroxisome Proliferator-Activated Receptor- Decreases Pancreatic Cancer Cell Invasion through Modulation of the Plasminogen Activator System

¹ Hirshberg Laboratory for Pancreatic Cancer Research, Department of Surgery and ² Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Guido Eibl, Hirshberg Laboratory for Pancreatic Cancer Research, Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, 675 Charles E. Young Drive South, MRL 2535, Los Angeles, CA 90095. Phone: 310-794-9577; Fax: 310-825-8975. E-mail: Geibl{at}mednet.ucla.edu

Cancer cell invasion and metastasis require the concerted action of several proteases that degrade extracellular matrix proteins and basement membranes. Recent reports suggest the plasminogen activator system plays a critical role in pancreatic cancer biology. In the present study, we determined the contribution of the plasminogen activator system to pancreatic cancer cell invasion in vitro. Moreover, the effect of peroxisome proliferator-activated receptor (PPAR)- ligands, which are currently in clinical use as antidiabetic drugs and interestingly seem to display antitumor activities, on pancreatic cancer cell invasion and the plasminogen activator system was assessed. Expression of components of the plasminogen activator system [i.e., urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1, and uPA receptor] was detected in six human pancreatic cancer cell lines. Inhibition of urokinase activity by specific synthetic compounds reduced baseline pancreatic cancer cell invasion. The PPAR- ligands 15-deoxy-^12,14-prostaglandin J₂ and ciglitazone also attenuated pancreatic cancer cell invasion. This effect was abrogated by dominant-negative PPAR- receptors and pharmacologic PPAR- inhibitors. Moreover, activation of PPAR- by ligands increased plasminogen activator inhibitor-1 and decreased uPA levels in pancreatic cancer cells, and this was accompanied by a reduction in total urokinase activity. The present study shows that the plasminogen activator system plays an integral role in pancreatic cancer cell invasion in vitro. Activation of the nuclear receptor PPAR- by ligands reduced pancreatic cancer cell invasion, which was largely mediated by modulation of the plasminogen activator system. These findings further underscore the potential role of PPAR- ligands as therapeutic agents in pancreatic cancer. (Mol Cancer Res 2006;4(3):159–67)

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