Exp Mol Med.
2012 Nov;44(11):653-664.
Kurarinone promotes TRAIL-induced apoptosis by inhibiting NF-kappaB-dependent cFLIP expression in HeLa cells
- Affiliations
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- 1Vascular 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
- 2Department of Rehabilitation Medicine, School of Medicine, Kangwon National University and Hospital, Chuncheon 200-701, Korea.
- 3Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon 200-701, Korea.
- 4Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-752, Korea.
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.
Keyword
MeSH Terms
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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
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