Title of article :
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
Author/Authors :
Yeoun Hee Kim، نويسنده , , Eun Mi Jung، نويسنده , , Tae-Jin Lee، نويسنده , , Sang-Hyun Kim، نويسنده , , Yung Hyun Choi، نويسنده , , Jeen-Woo Park، نويسنده , , Jong-Wook Park، نويسنده , , Kyeong Sook Choi، نويسنده , , Taeg Kyu Kwon، نويسنده ,
Issue Information :
روزنامه با شماره پیاپی سال 2008
Pages :
14
From page :
1055
To page :
1068
Abstract :
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 PPARγ-independent, because a dominant-negative mutant of PPARγ and a potent PPARγ 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.
Keywords :
TRAIL , Apoptosis , rosiglitazone , reactive oxygen species , c-FLIP , DR5 , free radicals
Journal title :
Free Radical Biology and Medicine
Serial Year :
2008
Journal title :
Free Radical Biology and Medicine
Record number :
521251
Link To Document :
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