Pro-MMP-2 Activation by the PPARgamma Agonist, Ciglitazone, Induces Cell Invasion Through the Generation of ROS and the Activation of ERK

FEBS Lett. 2007 Jul 10;581(17):3303-10. doi: 10.1016/j.febslet.2007.06.012. Epub 2007 Jun 19.


Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor modulating a variety of biological functions including cancer cell proliferation and differentiation. However, the role of PPARgamma and its ligands in tumor invasion is unclear. To evaluate a possible role for PPARgamma ligands in tumor invasion, we examined whether PPARgamma 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 (MT1-MMP) expression. The PPARgamma antagonist, GW9662 attenuated the ciglitazone-induced PPARgamma 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 PPARgamma 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 pro-MMP-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 PPARgamma-independent tumor cell invasion through ROS production and ERK activation in some types of cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Activation / drug effects*
  • Enzyme Precursors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fibrosarcoma / metabolism
  • Fibrosarcoma / pathology*
  • Gelatinases / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Matrix Metalloproteinase 14 / genetics
  • Metalloendopeptidases / metabolism*
  • Neoplasm Invasiveness
  • PPAR gamma / agonists*
  • Reactive Oxygen Species / metabolism*
  • Thiazolidinediones / pharmacology*
  • Tumor Cells, Cultured


  • Enzyme Precursors
  • PPAR gamma
  • Reactive Oxygen Species
  • Thiazolidinediones
  • Extracellular Signal-Regulated MAP Kinases
  • Gelatinases
  • Metalloendopeptidases
  • progelatinase
  • Matrix Metalloproteinase 14
  • ciglitazone