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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2727-2735.
Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-10-050807.
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Submitted October 8, 2006
Accepted November 9, 2006
Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF- B-regulated gene products and TAK1-mediated NF-B activation
Gautam Sethi, Kwang Seok Ahn, Manoj K. Pandey, and Bharat B. Aggarwal*
Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX
* Corresponding author; email: aggarwal{at}mdanderson.org.
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- B activation. We found that TNF induced the expression of gene products involved in anti-apoptosis (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-B, we postulated that celastrol mediates its effects by modulating the NF-B pathway. We found that celastrol suppressed both inducible and constitutive NF-B activation. Celastrol was found to inhibit the TNF-induced activation of IB kinase, IB phosphorylation, IB degradation, p65 nuclear translocation and phosphorylation; and NF-B -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-B activation. Overall, our results suggest that celastrol potentiates TNF-induced apoptosis and inhibits invasion through suppression of the NF-B pathway.
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