TY - JOUR
T1 - Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB-regulated gene products and TAK1-mediated NF-κB activation
AU - Sethi, Gautam
AU - Kwang, Seok Ahn
AU - Pandey, Manoj K.
AU - Aggarwal, Bharat B.
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2007/4/1
Y1 - 2007/4/1
N2 - Celastrol, a quinone methide triterpene derived from the medicinal plant Tripterygium wilfordii, has been used to treat chronic inflammatory and autoimmune diseases, but its mechanism is not well understood. Therefore, we investigated the effects of celastrol on cellular responses activated by TNF, a potent proinflammatory cytokine. Celastrol potentiated the apoptosis induced by TNF and chemotherapeutic agents and inhibited invasion, both regulated by NF-κB activation. We found that TNF induced the expression of gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2, Bcl-XL, c-FLIP, and survivin), proliferation (cyclin D1 and COX-2), invasion (MMP-9), and angiogenesis (VEGF) and that celastrol treatment suppressed their expression. Because these gene products are regulated by NF-κB, we postulated that celastrol mediates its effects by modulating the NF-κB pathway. We found that celastrol suppressed both inducible and constitutive NF-κB activation. Celastrol was found to inhibit the TNF-induced activation of IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 nuclear translocation and phosphorylation, and NF-κB-mediated reporter gene expression. Recent studies indicate that TNF-induced IKK activation requires activation of TAK1, and we indeed found that celastrol inhibited the TAK1-induced NF-κB activation. Overall, our results suggest that celastrol potentiates TNF-induced apoptosis and inhibits invasion through suppression of the NF-κB pathway.
AB - Celastrol, a quinone methide triterpene derived from the medicinal plant Tripterygium wilfordii, has been used to treat chronic inflammatory and autoimmune diseases, but its mechanism is not well understood. Therefore, we investigated the effects of celastrol on cellular responses activated by TNF, a potent proinflammatory cytokine. Celastrol potentiated the apoptosis induced by TNF and chemotherapeutic agents and inhibited invasion, both regulated by NF-κB activation. We found that TNF induced the expression of gene products involved in antiapoptosis (IAP1, IAP2, Bcl-2, Bcl-XL, c-FLIP, and survivin), proliferation (cyclin D1 and COX-2), invasion (MMP-9), and angiogenesis (VEGF) and that celastrol treatment suppressed their expression. Because these gene products are regulated by NF-κB, we postulated that celastrol mediates its effects by modulating the NF-κB pathway. We found that celastrol suppressed both inducible and constitutive NF-κB activation. Celastrol was found to inhibit the TNF-induced activation of IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 nuclear translocation and phosphorylation, and NF-κB-mediated reporter gene expression. Recent studies indicate that TNF-induced IKK activation requires activation of TAK1, and we indeed found that celastrol inhibited the TAK1-induced NF-κB activation. Overall, our results suggest that celastrol potentiates TNF-induced apoptosis and inhibits invasion through suppression of the NF-κB pathway.
UR - http://www.scopus.com/inward/record.url?scp=33947598693&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33947598693&partnerID=8YFLogxK
U2 - 10.1182/blood-2006-10-050807
DO - 10.1182/blood-2006-10-050807
M3 - Article
C2 - 17110449
AN - SCOPUS:33947598693
VL - 109
SP - 2727
EP - 2735
JO - Blood
JF - Blood
SN - 0006-4971
IS - 7
ER -