Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IκBα kinase and Akt activation
Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IκBα kinase and Akt activation
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DOI：
10.1124/mol.105.017400
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发表时间：
2006-01-01
影响因子：
3.6
通讯作者：
Aggarwal, BB
中科院分区：
文献类型：
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作者：
Aggarwal, S;Ichikawa, H;Aggarwal, BB
姜黄素（二阿魏酰甲烷），一种用于传统医学的抗炎剂，已被证明可以通过一种尚未完全理解的机制抑制细胞转化、增殖、侵袭、血管生成和转移。由于几个基因介导这些过程是由核因子-κ B（NF-κ B）调节，我们假设姜黄素介导其活性通过调节NF-κ B激活。实际上，我们的实验室先前已经显示姜黄素可以抑制由多种试剂诱导的NF-κ B活化（J Biol Chem 270：24995 - 50000，1995）。在本研究中，我们研究了姜黄素对NF-κ B和NF-κ B调节的基因表达的影响的机制。对20种不同的姜黄素类似物的筛选表明，姜黄素是抑制肿瘤坏死因子（TNF）诱导的NF-κ B活化的最有效的类似物。姜黄素以剂量依赖性方式抑制TNF诱导的NF-κ B依赖性报告基因表达。姜黄素还抑制由肿瘤坏死因子受体（TNFR）1、TNFR 2、NF-κ B诱导激酶、I κ B激酶复合物（IKK）和NF-κ B的p65亚基诱导的NF-κ B报告子活性。这种TNF诱导的NF-κ B调节的基因产物涉及细胞增殖[环加氧酶-2（考克斯-2）、细胞周期蛋白D1和c-myc]、抗凋亡[凋亡蛋白抑制剂（IAP）1、IAP 2、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-1 β转化酶抑制蛋白样抑制蛋白]与转移姜黄素还下调了血管内皮生长因子、基质金属蛋白酶-9和细胞间粘附分子-1的表达。TNF诱导的考克斯-2启动子活性被姜黄素阻断。我们发现姜黄素抑制TNF诱导的p65核转位，这与I κ B α激酶活性、I κ B α磷酸化、I κ B α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活化及其与IKK的关联。谷氨酰胺和二硫苏糖醇逆转姜黄素对TNF诱导的NF-κ B活化的影响。总之，我们的研究结果表明，姜黄素抑制NF-κ B B激活和NF-κ B调节的基因表达，通过抑制IKK和Akt激活。
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-kappa B (NF-kappa B), we have postulated that curcumin mediates its activity by modulating NF-kappa B activation. Indeed, our laboratory has shown previously that curcumin can suppress NF-kappa B 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-kappa B and NF-kappa 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-kappa B activation. Curcumin inhibited TNF-induced NF-kappa B-dependent reporter gene expression in a dose-dependent manner. Curcumin also suppressed NF-kappa B reporter activity induced by tumor necrosis factor receptor (TNFR) 1, TNFR2, NF-kappa B-inducing kinase, I kappa B kinase complex (IKK), and the p65 subunit of NF-kappa B. Such TNF-induced NF-kappa 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 beta-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 I kappa B alpha kinase activity, I kappa B alpha phosphorylation, I kappa B alpha 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-kappa B activation. Overall, our results indicated that curcumin inhibits NF-kappa B activation and NF-kappa B-regulated gene expression through inhibition of IKK and Akt activation.