Apoptosis induced by troglitazone is both peroxisome proliferator-activated receptor-gamma- and ERK-dependent in human non-small lung cancer cells

J Cell Physiol. 2006 Nov;209(2):428-38. doi: 10.1002/jcp.20738.

Abstract

The role of the peroxisome proliferator-activated receptor-gamma (PPARgamma) in cell differentiation, cell-cycle arrest, and apoptosis has attracted increasing attention. We have recently demonstrated that PPARgamma ligands-troglitazone (TGZ) induced apoptosis in lung cancer cells. In this report, we further studied the role of ERK1/2 in lung cancer cells treated by TGZ. The result demonstrated that TGZ induced PPARgamma and ERK1/2 accumulation in the nucleus, in which the co-localization of both proteins was found. The activation of ERK1/2 resulted in apoptosis via a mitochondrial pathway. Both PPARgamma siRNA and U0126, a specific inhibitor of ERK1/2, were able to block these effects of TGZ, suggesting that apoptosis induced by TGZ was PPARgamma and ERK1/2 dependent. Inhibition of ERK1/2 by U0126 also led to a significant decrease in the level of PPARgamma, indicating a positive cross-talk between PPARgamma and ERK1/2 or an auto-regulatory feedback mechanism to amplify the effect of ERK1/2 on cell growth arrest and apoptosis. In addition to ERK1/2, TGZ also activated Akt. Interestingly, inhibition of ERK1/2 prevented the activation of Akt whereas the suppression of Akt had no effect on ERK1/2, suggesting that Akt was not necessary for TGZ-PPARgamma-ERK pathway. However, the inhibition of Akt promoted the release of cytochrome c, suggesting the activation of Akt may have a negative effect on apoptosis induced by TGZ. In conclusion, our study has demonstrated that TGZ, a synthetic PPARgamma ligand, induced apoptosis in NCI-H23 lung cancer cells via a mitochondrial pathway and this pathway was PPARgamma and ERK1/2 dependent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Caspases / metabolism
  • Cell Differentiation / drug effects
  • Cell Nucleus / enzymology
  • Chromans / pharmacology*
  • Cytochromes c / metabolism
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Extracellular Signal-Regulated MAP Kinases / biosynthesis
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Humans
  • Membrane Potentials / drug effects
  • Mitochondrial Membranes / drug effects
  • Models, Biological
  • PPAR gamma / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Thiazolidinediones / pharmacology*
  • Troglitazone
  • Tumor Cells, Cultured

Substances

  • Chromans
  • PPAR gamma
  • Thiazolidinediones
  • Cytochromes c
  • Phosphatidylinositol 3-Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Caspases
  • Troglitazone