TY - JOUR T1 - Curcumin (Diferuloylmethane) Down-Regulates Expression of Cell Proliferation and Antiapoptotic and Metastatic Gene Products through Suppression of IκBα Kinase and Akt Activation JF - Molecular Pharmacology JO - Mol Pharmacol SP - 195 LP - 206 DO - 10.1124/mol.105.017400 VL - 69 IS - 1 AU - Sita Aggarwal AU - Haruyo Ichikawa AU - Yasunari Takada AU - Santosh K. Sandur AU - Shishir Shishodia AU - Bharat B. Aggarwal Y1 - 2006/01/01 UR - http://molpharm.aspetjournals.org/content/69/1/195.abstract N2 - 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-κB (NF-κB), we have postulated that curcumin mediates its activity by modulating NF-κB activation. Indeed, our laboratory has shown previously that curcumin can suppress NF-κB activation induced by a variety of agents (J Biol Chem270:24995-50000, 1995). In the present study, we investigated the mechanism by which curcumin manifests its effect on NF-κB and NF-κB-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-κB activation. Curcumin inhibited TNF-induced NF-κB-dependent reporter gene expression in a dose-dependent manner. Curcumin also suppressed NF-κB reporter activity induced by tumor necrosis factor receptor (TNFR)1, TNFR2, NF-κB-inducing kinase, IκB kinase complex (IKK), and the p65 subunit of NF-κB. Such TNF-induced NF-κB-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-xL, Bfl-1/A1, TNF receptor-associated factor 1, and cellular Fas-associated death domain protein-like interleukin-1β-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 IκBα kinase activity, IκBα phosphorylation, IκBα 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-κB activation. Overall, our results indicated that curcumin inhibits NF-κB activation and NF-κB-regulated gene expression through inhibition of IKK and Akt activation. ER -