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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. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-10-050807v1 109/7/2727    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sethi, G. Articles by Aggarwal, B. B. Search for Related Content PubMed PubMed Citation Articles by Sethi, G. Articles by Aggarwal, B. B. Related Collections Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS 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 Sethi1, Kwang Seok Ahn1, Manoj K. Pandey1, and Bharat B. Aggarwal1 1 Cytokine Research Laboratory, Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 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 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-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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. I. Idris, H. Libouban, H. Nyangoga, E. Landao-Bassonga, D. Chappard, and S. H. Ralston Pharmacologic inhibitors of I{kappa}B kinase suppress growth and migration of mammary carcinosarcoma cells in vitro and prevent osteolytic bone metastasis in vivo Mol. Cancer Ther., August 1, 2009; 8(8): 2339 - 2347. [Abstract] [Full Text] [PDF] K. B. Harikumar, A. B. Kunnumakkara, K. S. Ahn, P. Anand, S. Krishnan, S. Guha, and B. B. Aggarwal Modification of the cysteine residues in I{kappa}B{alpha} kinase and NF-{kappa}B (p65) by xanthohumol leads to suppression of NF-{kappa}B-regulated gene products and potentiation of apoptosis in leukemia cells Blood, February 26, 2009; 113(9): 2003 - 2013. [Abstract] [Full Text] [PDF] Y. 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