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

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Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) ligands are potential chemopreventive agents. Many studies have shown that PPARγ ligands induce apoptosis in various types of cancer cells including lung cancer cells. Some PPARγ 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 PPARγ 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 PPARγ ligand’s ability to enhance TRAIL-induced apoptosis. Thus, it appears that not only c-FLIP downregulation but also DR5 upregulation contribute to PPARγ ligand-mediated enhancement of TRAIL-induced apoptosis in human lung cancer cells. Both the PPARγ antagonist GW9662 and silencing PPARγ expression failed to diminish PPARγ ligand-induced DR5 upregulation or c-FLIP downregulation, indicating that PPARγ ligands modulate that expression of DR5 and c-FLIP through a PPARγ-independent mechanism. Collectively, we conclude that PPARγ ligands exert PPARγ-independent effects on inducing DR5 expression and downregulating c-FLIP levels, leading to enhancement of TRAIL-induced apoptosis.

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