title: PPARgamma ligands enhance TRAIL-induced apoptosis through DR5 upregulation and c-FLIP downregulation in human lung cancer cells.
abstract: 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.
authors.affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Yue
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists*; D034741:RNA, Small Interfering / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D008024:Ligands; D047495:PPAR gamma; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand