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

Tae Jin Lee, Hee Jung Um, Do Sik Min, Jong Wook Park, Kyeong Sook Choi, Taeg Kyu Kwon

Research output: Contribution to journalArticle

79 Citations (Scopus)

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-κB-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.

Original languageEnglish
Pages (from-to)1639-1649
Number of pages11
JournalFree Radical Biology and Medicine
Volume46
Issue number12
DOIs
Publication statusPublished - 2009 Jun 15

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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