Kurarinone promotes TRAIL-induced apoptosis by inhibiting NF-kappaB-dependent cFLIP expression in HeLa cells.
- Author:
Ok Won SEO
1
;
Jung Hwan KIM
;
Kwang Soon LEE
;
Kyu Sun LEE
;
Ji Hee KIM
;
Moo Ho WON
;
Kwon Soo HA
;
Young Guen KWON
;
Young Myeong KIM
Author Information
1. Vascular Homeostasis Laboratory, Departments of Molecular and Cellular Biochemistry and Institute of Medical Sciences, School of Medicine, Kangwon National University, Chuncheon 200-701, Korea. ymkim@kangwon.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
apoptosis;
CASP8 and FADD-Like apoptosis regulating protein;
kurarinone;
NF-kappaB;
TNF-related apoptosis-inducing ligand
- MeSH:
Antineoplastic Agents/*pharmacology;
Apoptosis/*drug effects;
CASP8 and FADD-Like Apoptosis Regulating Protein/*genetics/metabolism;
Caspase 3/metabolism;
Caspase 8/metabolism;
Drug Synergism;
Enzyme Activation/drug effects;
Flavonoids/*pharmacology;
Gene Expression/drug effects;
Gene Knockdown Techniques;
HeLa Cells;
Humans;
NF-kappa B/antagonists & inhibitors/*metabolism;
Protein Transport/drug effects;
RNA, Small Interfering/genetics;
Signal Transduction;
TNF-Related Apoptosis-Inducing Ligand/*physiology;
Up-Regulation/drug effects
- From:Experimental & Molecular Medicine
2012;44(11):653-664
- CountryRepublic of Korea
- Language:English
-
Abstract:
This study was designed to investigate the effects of the prenylated flavonoid kurarinone on TNF-related apoptosis inducing ligand (TRAIL)-induced apoptosis and its underlying mechanism. A low dose of kurarinone had no significant effect on apoptosis, but this compound markedly promoted tumor cell death through elevation of Bid cleavage, cytochrome c release and caspase activation in HeLa cells treated with TRAIL. Caspase inhibitors inhibited kurarinone-mediated cell death, which indicates that the cytotoxic effect of this compound is mediated by caspase-dependent apoptosis. The cytotoxic effect of kurarinone was not associated with expression levels of Bcl-2 and IAP family proteins, such as Bcl-2, Bcl-xL, Bid, Bad, Bax, XIAP, cIAP-1 and cIAP-2. In addition, this compound did not regulate the death-inducing receptors DR4 and DR5. On the other hand, kurarinone significantly inhibited TRAIL-induced IKK activation, IkappaB degradation and nuclear translocation of NF-kappaB, as well as effectively suppressed cellular FLICE-inhibitory protein long form (cFLIPL) expression. The synergistic effects of kurarinone on TRAIL-induced apoptosis were mimicked when kurarinone was replaced by the NF-kappaB inhibitor withaferin A or following siRNA-mediated knockdown of cFLIPL. Moreover, cFLIP overexpression effectively antagonized kurarinone-mediated TRAIL sensitization. These data suggest that kurarinone sensitizes TRAIL-induced tumor cell apoptosis via suppression of NF-kappaB-dependent cFLIP expression, indicating that this compound can be used as an anti-tumor agent in combination with TRAIL.
