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Endoplasmic reticulum stress mediates withaferin A-induced apoptosis in human renal carcinoma cells

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Author(s)
박종욱권택규
Alternative Author(s)
Park, Jong WookKwon, Taeg Kyu
Publication Year
2011
Keyword
Withaferin AEndoplasmic reticulum stressApoptosisCHOPUnfolded protein response
Abstract
The accumulation ofmisfolded proteins in the lumen of the endoplasmic reticulum(ER) results in cellular
stress that initiates a specialized response designated as the unfolded protein response. ER stress has
been implicated in a variety of common diseases, such as diabetes, ischemia and neurodegenerative dis-
orders. Withaferin A, a major chemical constituent of Withania somnifera, has been reported to inhibit
tumor cell growth. We show that withaferin A induced a dose-dependent apoptotic cell death in several
types of human cancer cells, as measured by FACS analysis and PARP cleavage. Treatment of Caki cells
with withaferin A induced a number of signature ER stress markers, including phosphorylation of eukary-
otic initiation factor-2a (eIF-2 a), ER stress-specific XBP1 splicing, and up-regulation of glucose-regulated
protein (GRP)-78. In addition, withaferin A caused up-regulation of CAAT/enhancer-binding protein-
homologous protein (CHOP), suggesting the induction of ER stress. Pretreatment with N-acetyl cysteine
(NAC) significantly inhibited withaferin A-mediated ER stress proteins and cell death, suggesting that
reactive oxygen species (ROS) mediate withaferin A-induced ER stress. Furthermore, CHOP siRNA or inhi-
bition of caspase-4 activity attenuated withaferin A-induced apoptosis. Taken together, the present study
provides strong evidence supporting an important role of the ER stress response in mediating withaferin
A-induced apoptosis. Keywords:
Withaferin A
Endoplasmic reticulum stress
Apoptosis
CHOP
Unfolded protein response
Department
Dept. of Immunology (면역학)
Publisher
School of Medicine
Citation
Toxicol In Vitro, Vol.25(3) : 692-698, 2011
Type
Article
ISSN
0887-2333
DOI
10.1016/j.tiv.2011.01.010
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/34656
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