Aggarwal Sita, Ichikawa Haruyo, Takada Yasunari, Sandur Santosh K, Shishodia Shishir, Aggarwal Bharat B
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009, USA.
Mol Pharmacol. 2006 Jan;69(1):195-206. doi: 10.1124/mol.105.017400. Epub 2005 Oct 11.
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-kappaB (NF-kappaB), we have postulated that curcumin mediates its activity by modulating NF-kappaB activation. Indeed, our laboratory has shown previously that curcumin can suppress NF-kappaB activation induced by a variety of agents (J Biol Chem 270:24995-50000, 1995). In the present study, we investigated the mechanism by which curcumin manifests its effect on NF-kappaB and NF-kappaB-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-kappaB activation. Curcumin inhibited TNF-induced NF-kappaB-dependent reporter gene expression in a dose-dependent manner. Curcumin also suppressed NF-kappaB reporter activity induced by tumor necrosis factor receptor (TNFR)1, TNFR2, NF-kappaB-inducing kinase, IkappaB kinase complex (IKK), and the p65 subunit of NF-kappaB. Such TNF-induced NF-kappaB-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-1beta-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 IkappaBalpha kinase activity, IkappaBalpha phosphorylation, IkappaBalpha 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-kappaB activation. Overall, our results indicated that curcumin inhibits NF-kappaB activation and NF-kappaB-regulated gene expression through inhibition of IKK and Akt activation.
姜黄素（二阿魏酰甲烷）是一种用于传统医学的抗炎剂，已被证明可通过一种尚未完全了解的机制抑制细胞转化、增殖、侵袭、血管生成和转移。由于介导这些过程的几个基因受核因子-κB（NF-κB）调控，我们推测姜黄素通过调节NF-κB激活来介导其活性。事实上，我们实验室先前已表明姜黄素可抑制多种试剂诱导的NF-κB激活（《生物化学杂志》270:24995 - 50000，1995年）。在本研究中，我们研究了姜黄素对NF-κB及其调控的基因表达产生影响的机制。对20种不同的姜黄素类似物进行筛选表明，姜黄素是抑制肿瘤坏死因子（TNF）诱导的NF-κB激活中最有效的类似物。姜黄素以剂量依赖的方式抑制TNF诱导的NF-κB依赖的报告基因表达。姜黄素还抑制肿瘤坏死因子受体（TNFR）1、TNFR2、NF-κB诱导激酶、IκB激酶复合物（IKK）和NF-κB的p65亚基诱导的NF-κB报告基因活性。此类TNF诱导的NF-κB调控的基因产物涉及细胞增殖[环氧合酶-2（COX-2）、细胞周期蛋白D1和c-myc]、抗凋亡[凋亡抑制蛋白（IAP）1、IAP2、X染色体连锁IAP、Bcl-2、Bcl-x（L）、Bfl-1/A1、TNF受体相关因子1和细胞Fas相关死亡结构域蛋白样白细胞介素-1β转换酶抑制蛋白样抑制蛋白]以及转移（血管内皮生长因子、基质金属蛋白酶-9和细胞间黏附分子-1）也被姜黄素下调。姜黄素消除了TNF诱导的COX-2启动子活性。我们发现姜黄素抑制TNF诱导的p65核转位，这与IκBα激酶活性、IκBα磷酸化、IκBα降解、p65磷酸化、p65核转位和p65乙酰化的顺序抑制相对应。姜黄素还抑制TNF诱导的Akt激活及其与IKK的结合。谷胱甘肽和二硫苏糖醇逆转了姜黄素对TNF诱导的NF-κB激活的作用。总体而言，我们的结果表明姜黄素通过抑制IKK和Akt激活来抑制NF-κB激活和NF-κB调控的基因表达。
