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Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP.

Authors
Lee, TJ; Um, HJ; Min, do S; Park, JW; Choi, KS; Kwon, TK
Citation
Free radical biology & medicine, 46(12):1639-1649, 2009
Journal Title
Free radical biology & medicine
ISSN
0891-58491873-4596
Abstract
Withaferin A (Wit A) has reportedly shown cytotoxicity in a variety of tumor cell lines. Here, we show that cotreatment with subtoxic doses of Wit A and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in human renal cancer cells, Caki cells, but not in human normal mesangial cells. Moreover, the combined treatment with Wit A and TRAIL dramatically induces apoptosis in various cancer cell types, suggesting that this combined treatment might offer an attractive strategy for safely treating human cancers. Treatment of Caki cells with Wit A up-regulated death receptor 5 (DR5) in a C/EBP homologous protein (CHOP)-dependent manner. Interestingly, a Wit A-induced increase in ROS levels preceded the up-regulation of CHOP and DR5. The involvement of ROS in CHOP-mediated DR5 up-regulation was confirmed by the result that pretreatment with an antioxidant, NAC or catalase, inhibited Wit A-induced up-regulation of both CHOP and DR5. We also found that Wit A treatment down-regulated c-FLIP via NF-kappaB-mediated transcriptional control as well as ROS signaling pathways. Taken together, our results show that DR5 up-regulation and c-FLIP down-regulation contribute to the sensitizing effect of Wit A on TRAIL-mediated apoptosis in cancer cells.
MeSH terms
Apoptosis/drug effects*CASP8 and FADD-Like Apoptosis Regulating Protein/drug effects*CASP8 and FADD-Like Apoptosis Regulating Protein/metabolismDown-Regulation/drug effectsDrug Screening Assays, AntitumorErgosterol/analogs & derivatives*Ergosterol/pharmacologyGene Expression Regulation/drug effects*HumansNF-kappa B/antagonists & inhibitorsNF-kappa B/metabolismReactive Oxygen Species/metabolism*Receptors, TNF-Related Apoptosis-Inducing Ligand/drug effects*Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolismSensitivity and SpecificitySignal Transduction/drug effectsTNF-Related Apoptosis-Inducing Ligand/pharmacology*Tumor Cells, CulturedUp-Regulation/drug effects
DOI
10.1016/j.freeradbiomed.2009.03.022
PMID
19345731
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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