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Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

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Author(s)
Tae-Jin LeeHee Jung UmDo Sik MinJong-Wook ParkKyeong Sook ChoiTaeg Kyu Kwon
Keimyung Author(s)
Park, Jong WookKwon, Taeg Kyu
Department
Dept. of Immunology (면역학)
Journal Title
Free Radical Biology and Medicine
Issued Date
2009
Volume
46
Issue
12
Abstract
Withaferin A (Wit A) has reportedly shown cytotoxicity in a variety of tumor cell lines. Here, we show
that cotreatment with subtoxic doses of Wit A and tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) induces apoptosis in human renal cancer cells, Caki cells, but not in human normal
mesangial cells. Moreover, the combined treatment with Wit A and TRAIL dramatically induces apoptosis
in various cancer cell types, suggesting that this combined treatment might offer an attractive strategy for
safely treating human cancers. Treatment of Caki cells with Wit A up-regulated death receptor 5 (DR5) in
a C/EBP homologous protein (CHOP)-dependent manner. Interestingly, a Wit A-induced increase in ROS
levels preceded the up-regulation of CHOP and DR5. The involvement of ROS in CHOP-mediated DR5 upregulation
was confirmed by the result that pretreatment with an antioxidant, NAC or catalase, inhibited
Wit A-induced up-regulation of both CHOP and DR5. We also found that Wit A treatment down-regulated
c-FLIP via NF-κB-mediated transcriptional control as well as ROS signaling pathways. Taken together, our
results show that DR5 up-regulation and c-FLIP down-regulation contribute to the sensitizing effect of
Wit A on TRAIL-mediated apoptosis in cancer cells.
Keimyung Author(s)(Kor)
박종욱
권택규
Publisher
School of Medicine
Citation
Tae-Jin Lee et al. (2009). Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen
species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP. Free Radical Biology and Medicine, 46(12), 1639–1649. doi: 10.1016/j.freeradbiomed.2009.03.022
Type
Article
ISSN
0891-5849
Source
http://lps3.linkinghub.elsevier.com.proxy.dsmc.or.kr/retrieve/pii/S0891-5849(09)00177-4
DOI
10.1016/j.freeradbiomed.2009.03.022
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/35756
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
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