Rosiglitazone promotes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP.
Death receptor 5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In this study, we show that rosiglitazone sensitizes human renal cancer cells to TRAIL-mediated apoptosis, but not normal human mesangial cells. Furthermore, because rosiglitazone-enhanced TRAIL-mediated apoptosis is induced in various types of cancer cells but is not interrupted by Bcl-2 overexpression, this combinatory treatment may provide an attractive strategy for cancer treatment. We found that treatment with rosiglitazone significantly induces DR5 expression at both its mRNA and its protein levels, accompanying the generation of reactive oxygen species (ROS). Both treatment with DR5/Fc chimeric protein and silencing of DR5 expression using small interfering RNAs attenuated rosiglitazone plus TRAIL-induced apoptosis, showing the critical role of DR5 in this cell death. Pretreatment with GSH significantly inhibited rosiglitazone-induced DR5 up-regulation and the cell death induced by the combined treatment with rosiglitazone and TRAIL, suggesting that ROS mediate rosiglitazone-induced DR5 up-regulation, contributing to TRAIL-mediated apoptosis. However, both DR5 up-regulation and sensitization of TRAIL-mediated apoptosis induced by rosiglitazone are likely PPARgamma-independent, because a dominant-negative mutant of PPARgamma and a potent PPARgamma inhibitor, GW9662, failed to block DR5 induction and apoptosis. Interestingly, we also found that rosiglitazone treatment induced down-regulation of cellular FLICE-inhibitory protein (c-FLIPs), and ectopic expression of c-FLIPs attenuated rosiglitazone plus TRAIL-mediated apoptosis, demonstrating the involvement of c-FLIPs in this apoptosis. Taken together, the results of this study demonstrate that rosiglitazone enhances TRAIL-induced apoptosis in various cancer cells by ROS-mediated DR5 up-regulation and down-regulation of c-FLIPs.
Kim
Yeoun Hee
YH
Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea.
Jung
Eun Mi
EM
Lee
Tae-Jin
TJ
Kim
Sang Hyun
SH
Choi
Yung Hyun
YH
Park
Jeen Woo
JW
Park
Jong-Wook
JW
Choi
Kyeong Sook
KS
Kwon
Taeg Kyu
TK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation
D000970:Antineoplastic Agents; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D045162:Thiazolidinediones; D000077154:Rosiglitazone