Kurarinone promotes TRAIL-induced apoptosis by inhibiting NF-κB-dependent cFLIP expression in HeLa cells

• Published in: Experimental & molecular medicine 2012, 44(11), , pp.653-664
• Main Authors: Seo, Ok-Won, Kim, Jung Hwan, Lee, Kwang-Soon, Lee, Kyu-Sun, Kim, Ji-Hee, Won, Moo-Ho, Ha, Kwon-Soo, Kwon, Young-Guen, Kim, Young-Myeong
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biomedical and Life Sciences; Biomedicine; CASP8 and FADD-Like Apoptosis Regulating Protein - genetics; CASP8 and FADD-Like Apoptosis Regulating Protein - 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; Medical Biochemistry; Molecular Medicine; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Original; Protein Transport - drug effects; RNA, Small Interfering - genetics; Signal Transduction; Stem Cells; TNF-Related Apoptosis-Inducing Ligand - physiology; Up-Regulation - drug effects; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.3858/emm.2012.44.11.074

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-x L , 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, IκB degradation and nuclear translocation of NF-κB, as well as effectively suppressed cellular FLICE-inhibitory protein long form (cFLIP L ) expression. The synergistic effects of kurarinone on TRAIL-induced apoptosis were mimicked when kurarinone was replaced by the NF-κB inhibitor withaferin A or following siRNA-mediated knockdown of cFLIP L . Moreover, cFLIP overexpression effectively antagonized kurarinone-mediated TRAIL sensitization. These data suggest that kurarinone sensitizes TRAIL-induced tumor cell apoptosis via suppression of NF-κB-dependent cFLIP expression, indicating that this compound can be used as an anti-tumor agent in combination with TRAIL.