PPARgamma ligands enhance TRAIL-induced apoptosis through DR5 upregulation and c-FLIP downregulation in human lung cancer cells

Cancer Biol Ther. 2007 Jan;6(1):99-106. doi: 10.4161/cbt.6.1.3555.


Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands are potential chemo-preventive agents. Many studies have shown that PPARy ligands induce apoptosis in various types of cancer cells including lung cancer cells. Some PPAR gamma ligands have been shown to downregulate c-FLIP expression and thus enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in some cancer cell lines. In the current study, we further show that PPARy ligands induced the expression of death receptor 5 (DR5) and increased DR5 distribution at the cell surface in addition to reducing c-FLIP levels in human lung cancer cells. These agents cooperated with TRAIL to enhance induction of apoptosis in human lung cancer cells. Both overexpression of c-FLIP and knockdown of DR5 abrogated PPARgamma ligand's ability to enhance TRAIL-induced apoptosis. Thus, it appears that not only c-FLIP downregulation but also DR5 upregulation contribute to PPARy ligand-mediated enhancement of TRAIL-induced apoptosis in human lung cancer cells. Both the PPARgamma antagonist GW9662 and silencing PPARgamma expression failed to diminish PPARgamma ligand-induced DR5 upregulation or c-FLIP downregulation, indicating that PPARy ligands modulate the expression of DR5 and c-FLIP through a PPARy-independent mechanism. Collectively, we conclude that PPARy ligands exert PPARy-independent effects on inducing DR5 expression and downregulating c-FLIP levels, leading to enhancement of TRAIL-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Cell Proliferation / drug effects
  • Down-Regulation
  • Humans
  • Ligands
  • Lung Neoplasms / metabolism*
  • PPAR gamma / agonists*
  • RNA, Small Interfering / pharmacology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Tumor Cells, Cultured
  • Up-Regulation


  • Antineoplastic Agents
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Ligands
  • PPAR gamma
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand