Silibinin sensitizes human glioma cells to TRAIL-Mediated apoptosis via DR5 up-regulation and down-regulation of c-FLIP and survivin

被引:122
作者
Son, Yong-Gyu
Kim, Eun Hee
Kim, Jin Yeop
Kim, Seung U.
Kwon, Taeg Kyu
Yoon, A-Rum
Yun, Chae-Ok
Choi, Kyeong Sook [1 ]
机构
[1] Ajou Univ, Sch Med, Inst Med Sci, Dept Mol Sci & Technol, Suwon 441749, South Korea
[2] Ajou Univ, Sch Med, Brain Dis Res Ctr, Suwon 441749, South Korea
[3] Keimyung Univ, Sch Med, Dept Immunol, Taegu, South Korea
[4] Yonsei Univ, Coll Med, Ctr Canc, Inst Canc Res, Seoul 120749, South Korea
关键词
D O I
10.1158/0008-5472.CAN-07-0407
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Silibinin, a flavonoid isolated from Silybum marianum, has been reported to have cancer chemopreventive and therapeutic effects. Here, we show that treatment with subtoxic doses of silibinin in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces rapid apoptosis in TRAIL-resistant glioma cells, but not in human astrocytes, suggesting that this combined treatment may offer an attractive strategy for safely treating gliomas. Although the proteolytic processing of procaspase-3 by TRAIL was partially blocked in glioma cells, cotreatment with silibinin efficiently recovered TRAIL-induced caspase activation in these cells. Silibinin treatment up-regulated DR5, a death receptor of TRAIL, in a transcription factor CHOP-dependent manner. Furthermore, treatment with silibinin down-regulated the protein levels of the antiapoptotic proteins FLIPL, FLIPS, and survivin through proteasome-mediated degradation. Taken together, our results show that the activity of silibinin to modulate multiple components in the death receptor-mediated apoptotic pathway is responsible for its ability to recover TRAIL sensitivity in TRAIL-resistant glioma cells.
引用
收藏
页码:8274 / 8284
页数:11
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