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Curcumin (Diferuloylmethane) Down-Regulates Expression of Cell Proliferation and Antiapoptotic and Metastatic Gene Products through Suppression of IB Kinase and Akt Activation

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

Curcumin (diferuloylmethane), an anti-inflammatory agent used in traditional medicine, has been shown to suppress cellular transformation, proliferation, invasion, angiogenesis, and metastasis through a mechanism not fully understood. Because several genes that mediate these processes are regulated by nuclear factor-B (NF-B), we have postulated that curcumin mediates its activity by modulating NF-B activation. Indeed, our laboratory has shown previously that curcumin can suppress NF-B activation induced by a variety of agents (J Biol Chem 270:24995-50000, 1995[Abstract/Free Full Text]). In the present study, we investigated the mechanism by which curcumin manifests its effect on NF-B and NF-B-regulated gene expression. Screening of 20 different analogs of curcumin showed that curcumin was the most potent analog in suppressing the tumor necrosis factor (TNF)-induced NF-B activation. Curcumin inhibited TNF-induced NF-B-dependent reporter gene expression in a dose-dependent manner. Curcumin also suppressed NF-B reporter activity induced by tumor necrosis factor receptor (TNFR)1, TNFR2, NF-B-inducing kinase, IB kinase complex (IKK), and the p65 subunit of NF-B. Such TNF-induced NF-B-regulated gene products involved in cellular proliferation [cyclooxygenase-2 (COX-2), cyclin D1, and c-myc], antiapoptosis [inhibitor of apoptosis protein (IAP)1, IAP2, X-chromosome-linked IAP, Bcl-2, Bcl-x_L, Bfl-1/A1, TNF receptor-associated factor 1, and cellular Fas-associated death domain protein-like interleukin-1-converting enzyme inhibitory protein-like inhibitory protein], and metastasis (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1) were also down-regulated by curcumin. COX-2 promoter activity induced by TNF was abrogated by curcumin. We found that curcumin suppressed TNF-induced nuclear translocation of p65, which corresponded with the sequential suppression of IB kinase activity, IB phosphorylation, IB degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acetylation. Curcumin also inhibited TNF-induced Akt activation and its association with IKK. Glutathione and dithiothreitol reversed the effect of curcumin on TNF-induced NF-B activation. Overall, our results indicated that curcumin inhibits NF-B activation and NF-B-regulated gene expression through inhibition of IKK and Akt activation.

Address correspondence to: Dr. Bharat B. Aggarwal, Department of Experimental Therapeutics, Box 143, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009. E-mail: aggarwal{at}mdanderson.org

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