HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nair, A. S. Articles by Aggarwal, B. B. Search for Related Content PubMed PubMed Citation Articles by Nair, A. S. Articles by Aggarwal, B. B.

Deguelin, an Akt Inhibitor, Suppresses IB Kinase Activation Leading to Suppression of NF-B-Regulated Gene Expression, Potentiation of Apoptosis, and Inhibition of Cellular Invasion¹

Department of Experimental Therapeutics, Cytokine Research Laboratory, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030

Deguelin, a constituent of the bark of the African plant Mundulea sericea (Leguminosae), exhibits antiproliferative and anticarcinogenic activities through a mechanism that is not well understood. Because various steps in carcinogenesis are regulated by NF-B, we postulated that the activity of deguelin is mediated through this transcription factor. We found that deguelin suppressed NF-B activation induced by carcinogens, tumor promoters, growth factors, and inflammatory stimuli. This suppression was not cell-type specific, because NF-B activation was suppressed in both lymphoid and epithelial cells. Moreover, constitutive NF-B activation was also blocked by deguelin. The suppression of TNF-induced NF-B activation by deguelin occurred through the inhibition of the activation of IB kinase, leading to sequential suppression of IB phosphorylation, IB degradation, p65 phosphorylation, p65 nuclear translocation, and NF-B-dependent reporter gene expression. Deguelin also suppressed the NF-B reporter activity induced by TNFR1, TNFR-associated death domain, TNFR-associated factor 2, and IB kinase, but not that induced by p65. The inhibition of NF-B activation thereby led to the down-regulation of gene products involved in cell survival, proliferation, and invasion. Suppression of these gene products by deguelin enhanced the apoptosis induced by TNF and chemotherapeutic agents and suppressed TNF-induced cellular invasion. Our results demonstrate that deguelin inhibits the NF-B activation pathway, which may explain its role in the suppression of carcinogenesis and cellular proliferation.

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.

¹ This work was supported by funds from the Clayton Foundation for Research (to B.B.A.), Department of Defense U.S. Army Breast Cancer Research Program Grant BC010610 (to B.B.A.), P01 Grant CA-91844 from the National Institutes of Health on lung chemoprevention (to B.B.A.), and P50CA-97007 Head and Neck Specialized Program of Research Excellence Grant from the National Institutes of Health (to B.B.A.).

² Address correspondence and reprint requests to Dr. Bharat B. Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, Box 143, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. E-mail address: aggarwal{at}mdanderson.org

³ Abbreviations used in this paper: COX, cyclooxygenase; ALLN, N-Ac-leu-leu-norleucinal; CSC, cigarette smoke condensate; IAP, inhibitor of apoptosis protein; IKK, IB kinase; MMP, matrix metalloproteinase; NIK, NF-B-inducing kinase; PARP, polyadenosylribose polymerase; SEAP, secretory alkaline phosphatase; TRADD, TNFR-associated death domain; TRAF, TNFR-associated factor; XIAP, X-linked inhibitor of apoptosis protein; zVAD-FMK, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone.

This article has been cited by other articles:

				J. L. Williams, P. Ji, N. Ouyang, X. Liu, and B. Rigas NO-donating aspirin inhibits the activation of NF-{kappa}B in human cancer cell lines and Min mice Carcinogenesis, February 1, 2008; 29(2): 390 - 397. [Abstract] [Full Text] [PDF]