Dicoumarol sensitizes renal cell carcinoma Caki cells to TRAIL-induced apoptosis through down-regulation of Bcl-2, Mcl-1 and c-FLIP in a NQO1-independent manner.
In the study, we investigated the effect of dicoumarol, an anti-coagulant agent with the inhibitory activity of NAD(P)H quinone oxidoreductase 1 (NQO1), on TRAIL-induced apoptosis in renal cancer cell. Combined treatment with dicoumarol and TRAIL significantly induced apoptosis in various human renal carcinoma cells including Caki, ACHN, and A498, but not in normal human skin fibroblasts (HSF) and mouse kidney cells (TMCK-1). When we elucidated the relevance of NQO1 in dicoumarol plus TRAIL-mediated apoptosis, both ES936 (a NQO1 inhibitor) and knockdown of NQO1 with siRNA had no effect on TRAIL-mediated apoptosis, suggesting that the stimulating effect of dicoumarol on TRAIL-mediated apoptosis is independent of NQO1 activity. We found that dicoumarol transcriptionally down-regulated Bcl-2 expression via inhibition of NF-κB and CREB activity, whereas it down-regulated Mcl-1 and c-FLIP expression at the post-translational level. Overexpression of Bcl-2, Mcl-1, or c-FLIP overcame the dicoumarol plus TRAIL-induced apoptosis, indicating that down-regualtion of these anti-apoptotic proteins may critically contribute to the sensitizing effect of dicoumarol on TRAIL-mediated apoptosis.
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Eun Jung
EJ
Park
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Kyoung-Jin
KJ
Min
Department of Biomedical Sciences, Ajou University School of Medicine, 5 Woncheon-Dong, Paldal-Gu, Suwon 442-749, South Korea.
Kyeong Sook
KS
Choi
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea. Electronic address: kwontk@dsmc.or.kr.
Taeg Kyu
TK
Kwon
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis / Q000378:metabolism; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D001728:Dicumarol / Q000494:pharmacology*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D045563:Indolequinones / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000378:metabolism*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
C444919:5-methoxy-1,2-dimethyl-3-((4-nitrophenoxy)methyl)indole-4,7-dione; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C497249:DDIT3 protein, human; D004791:Enzyme Inhibitors; D045563:Indolequinones; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051742:Transcription Factor CHOP; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D050882:CREB-Binding Protein; C494363:CREBBP protein, human
Bcl-2; Dicoumarol; Mcl-1; NQO1; TRAIL; c-FLIP