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

Fingerprint

TNF-Related Apoptosis-Inducing Ligand Receptors
Reactive Oxygen Species
Up-Regulation
Down-Regulation
Transcription Factor CHOP
Apoptosis
Cells
Neoplasms
Mesangial Cells
withaferin A
Cytotoxicity
Tumor Cell Line
Renal Cell Carcinoma
Catalase
Tumors
Tumor Necrosis Factor-alpha
Antioxidants
Ligands

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

Cite this

@article{36db1d76e50c42d0b7c23b18725d0990,
title = "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-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.",
author = "Lee, {Tae Jin} and Um, {Hee Jung} and Min, {Do Sik} and Park, {Jong Wook} and Choi, {Kyeong Sook} and Kwon, {Taeg Kyu}",
year = "2009",
month = "6",
day = "15",
doi = "10.1016/j.freeradbiomed.2009.03.022",
language = "English",
volume = "46",
pages = "1639--1649",
journal = "Free Radical Biology and Medicine",
issn = "0891-5849",
publisher = "Elsevier Inc.",
number = "12",

}

Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP. / Lee, Tae Jin; Um, Hee Jung; Min, Do Sik; Park, Jong Wook; Choi, Kyeong Sook; Kwon, Taeg Kyu.

In: Free Radical Biology and Medicine, Vol. 46, No. 12, 15.06.2009, p. 1639-1649.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Withaferin A sensitizes TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 and down-regulation of c-FLIP

AU - Lee, Tae Jin

AU - Um, Hee Jung

AU - Min, Do Sik

AU - Park, Jong Wook

AU - Choi, Kyeong Sook

AU - Kwon, Taeg Kyu

PY - 2009/6/15

Y1 - 2009/6/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=67349228750&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67349228750&partnerID=8YFLogxK

U2 - 10.1016/j.freeradbiomed.2009.03.022

DO - 10.1016/j.freeradbiomed.2009.03.022

M3 - Article

C2 - 19345731

AN - SCOPUS:67349228750

VL - 46

SP - 1639

EP - 1649

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

SN - 0891-5849

IS - 12

ER -