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J. Biol. Chem., Vol. 279, Issue 6, 4750-4759, February 6, 2004

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Flavopiridol Inhibits NF-B Activation Induced by Various Carcinogens and Inflammatory Agents through Inhibition of IB Kinase and p65 Phosphorylation

ABROGATION OF CYCLIN D1, CYCLOOXYGENASE-2, AND MATRIX METALLOPROTEASE-9^*

Yasunari Takada and Bharat B. Aggarwal

From the Cytokine Research Laboratory, Departments of Bioimmunotherapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Flavopiridol, a synthetic flavone closely related to a compound originally isolated from the stem bark of the native Indian plant Dysoxylum binectariferum, has been found to inhibit cyclin-dependent kinases, induce apoptosis, suppress inflammation, and modulate the immune response. Because several genes in which expression is altered by flavopiridol are regulated by NF-B, we propose that this flavone must affect the activation of NF-B. For this report, we investigated the effect of flavopiridol on NF-B activation by various carcinogens and inflammatory agents. Flavopiridol suppressed tumor necrosis factor (TNF)-activation of NF-B in a dose- and time-dependent manner in several cell types, with optimum inhibition occurring upon treatment of cells with 100 nM flavopiridol for 6 h. This effect was mediated through inhibition of IB kinase, phosphorylation, ubiquitination, and degradation of IB (an inhibitor of NF-B), and suppression of phosphorylation, acylation, and nuclear translocation of the p65 subunit of NF-B. Besides TNF, flavopiridol also suppressed NF-B activated by a carcinogen (cigarette smoke condensate), tumor promoters (phorbol myristate acetate and okadaic acid), and an inflammatory agent (H₂O₂). TNF-induced NF-B-dependent reporter gene transcription was also suppressed by this flavone. NF-B reporter activity induced by TNF receptor 1, TNF receptor-associated death domain, TNF receptor-associated factor-2, NF-B-inducing kinase, and IB kinase, were all blocked by flavopiridol but not that activated by p65. Furthermore, flavopiridol suppressed TNF-induced activation of Akt. Flavopiridol also inhibited the expression of the TNF-induced NF-B-regulated gene products cyclin D1, cyclooxygenase-2, and matrix metalloproteinase-9. Overall, our results indicated that flavopiridol inhibits activation of NF-B and NF-B-regulated gene expression, which may explain the ability of flavopiridol to suppress inflammation, modulate the immune response, and regulate cell growth.

Received for publication, April 30, 2003 , and in revised form, November 10, 2003.

^* This work was supported in part by the Clayton Foundation for Research (to B. B. A.), Department of Defense United States Army Breast Cancer Research Program Grant BC010610 (to B. B. A.), a PO1 Grant CA91844 from the National Institutes of Health on Lung Cancer Chemoprevention (to B. B. A.), and a P50 Head and Neck SPORE Grant from the National Institutes of Health (to B. B. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 713-792-3503/6459; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

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