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

Abstract

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 proliferatoractivated 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 J 2 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)

Hyperglycemia enhances the invasive and migratory activity of pancreatic cancer cells via hydrogen peroxide

“…Recent reports suggest the uPA system plays a critical role in pancreatic cancer biology. Peroxisome proliferator-activated receptor (PPAR)-Á ligands, which are currently in clinical use as antidiabetic drugs, seem to display antitumor activities on pancreatic cancer cell invasion and the plasminogen activator system was assessed (35). Hydrogen peroxide could up-regulate uPA expression in many cancer cell lines and this up-regulation is attenuated by ROS scavenger (17,18).…”

Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor γ involves angiogenesis inhibition

“…PPARγ plays an important role in insulin sensitization and differentiation of adipocytes, monocytes and macrophages [5] . Activation of PPARγ can also induce growth inhibition in human prostate cancer cells, colon cancer cells, gastric cancer cells [10] , pancreatic cancer cells [12][13][14][15][16][17] and liposarcoma cells [18] . The expression of PPARγ and its role in human pancreatic carcinoma have not been fully elucidated.…”

“…It has been shown that PPARγ gene expression is observed in a variety of tissues, including adipose tissue and tumor tissue. Some in vitro studies have recently reported that PPARγ activation has inhibitory effects on the growth of pancreatic carcinoma cells [13][14][15] , probably due to its up-regulation of cellular apoptosis and its down-regulation of tumor invasion [16][17][18] . However, little attention has previously been paid to PPARγ action on the growth of pancreatic carcinoma in vivo, especially its regulation action on tumor angiogenesis.…”

PPARγ agonists prevent TGFβ1/Smad3-signaling in human hepatic stellate cells

“…Although PPARγ does not block PAI-1 expression in all cells (11)(12)(13), an inhibitory effect on TGFβ1-ALK5 induction of PAI-1 has also been demonstrated in fat cells. Interestingly, PPARγ mediated repression of PAI-1 expression in fat cells promotes adipocytic differentiation (2,14).…”