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

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.

• Authors: Tae-Jin Lee, Hee Jung Um, Do Sik Min, Jong-Wook Park, Kyeong Sook Choi, Taeg Kyu Kwon
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 46 Issue 12 Pg. 1639-49 (Jun 15 2009) ISSN: 1873-4596 [Electronic] United States
• PMID: 19345731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CASP8 and FADD-Like Apoptosis Regulating Protein
• NF-kappa B
• Reactive Oxygen Species
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Withanolides
• withaferin A
• Ergosterol

Topics

• Apoptosis (drug effects)
• CASP8 and FADD-Like Apoptosis Regulating Protein (drug effects, metabolism)
• Down-Regulation (drug effects)
• Drug Screening Assays, Antitumor
• Ergosterol (analogs & derivatives, pharmacology)
• Gene Expression Regulation (drug effects)
• Humans
• NF-kappa B (antagonists & inhibitors, metabolism)
• Reactive Oxygen Species (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (drug effects, metabolism)
• Sensitivity and Specificity
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Tumor Cells, Cultured
• Up-Regulation (drug effects)
• Withanolides