Pro-MMP-2 activation by the PPAR gamma agonist, ciglitazone, induces cell invasion through the generation of ROS and the activation of ERK

Abstract

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor modulating a variety of biological functions including cancer cell proliferation and differentiation. However, the role of PPAR gamma and its ligands in tumor invasion is unclear. To evaluate a possible role for PPAR gamma ligands in tumor invasion, we examined whether PPAR gamma agonists including pioglitazone, troglitazone, rosiglitazone, and ciglitazone could affect the activity of matrix metalloproteinases (MMPs) in the HT1080 cell line, a well-studied and well-characterized cell line for MMP research. The gelatin zymography assay showed that ciglitazone activated pro-MMP-2 significantly. In addition, ciglitazone increased the expression of MMP-2, which was accompanied by an increase of membrane type 1-MMP (MT 1-MMP) expression. The PPAR gamma antagonist, GW9662 attenuated the ciglitazone-induced PPAR gamma activation but it did not affect the pro-MMP2 activation by ciglitazone, suggesting that the action of ciglitazone on the pro-MMP-2 activation bypassed the PPAR gamma pathway. Antioxidants and various inhibitors of signal transduction were used to investigate the mechanism of ciglitazone-induced pro-MMP-2 activation. We found that the sustained production of reactive oxygen species (ROS) was required for pro-MMP-2 activation by ciglitazone. We also found that PB98059, an inhibitor of MEK-ERK, significantly blocked ciglitazone-induced proMMP-2 activation and that extracellular signal-regulated kinase (ERK) was hyperphosphorylated by ciglitazone. Moreover, cell invasion was significantly increased by ciglitazone in the HT1080 cell lines, whereas cell motility was not affected. This study suggests that ciglitazone-induced pro-MMP-2 activation increases PPAR gamma-independent tumor cell invasion through ROS production and ERK activation in some types of cancer cells. (C) 2007 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.