Takada Yasunari, Murakami Akira, Aggarwal Bharat B
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston, TX 77030, USA.
Oncogene. 2005 Oct 20;24(46):6957-69. doi: 10.1038/sj.onc.1208845.
Zerumbone found in subtropical ginger Zingiber zerumbet Smith exhibits antiproliferative and antiinflammatory activities but underlying molecular mechanisms are poorly understood. As several genes that regulate proliferation and apoptosis are regulated by nuclear factor (NF)-kappaB, we hypothesized that zerumbone mediates its activity through the modulation of NF-kappaB activation. We found that zerumbone suppressed NF-kappaB activation induced by tumor necrosis factor (TNF), okadaic acid, cigarette smoke condensate, phorbol myristate acetate, and H2O2 and that the suppression was not cell type specific. Interestingly, alpha-humulene, a structural analogue of zerumbone lacking the carbonyl group, was completely inactive. Besides being inducible, constitutively active NF-kappaB was also inhibited. NF-kappaB inhibition by zerumbone correlated with sequential suppression of the IkappaBalpha kinase activity, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and p65 acylation. Zerumbone also inhibited the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK but not that activated by the p65 subunit of NF-kappaB. NF-kappaB-regulated gene products, such as cyclin D1, COX-2, MMP-9, ICAM-1, c-Myc, survivin, IAP1, IAP2, XIAP, Bcl-2, Bcl-xL, Bfl-1/A1, TRAF1 and FLIP, were all downregulated by zerumbone. This downregulation led to the potentiation of apoptosis induced by cytokines and chemotherapeutic agents. Zerumbone's inhibition of expression of these NF-kappaB-regulated genes also correlated with the suppression of TNF-induced invasion activity. Overall, our results indicated that zerumbone inhibits the activation of NF-kappaB and NF-kappaB-regulated gene expression induced by carcinogens and that this inhibition may provide a molecular basis for the prevention and treatment of cancer by zerumbone.
在亚热带植物莪术（Zingiber zerumbet Smith）中发现的姜酮醇具有抗增殖和抗炎活性，但其潜在的分子机制尚不清楚。由于几个调控增殖和凋亡的基因受核因子（NF）-κB调节，我们推测姜酮醇通过调节NF-κB的激活来介导其活性。我们发现姜酮醇可抑制由肿瘤坏死因子（TNF）、冈田酸、香烟烟雾冷凝物、佛波酯和H2O2诱导的NF-κB激活，且这种抑制作用不具有细胞类型特异性。有趣的是，姜酮醇缺乏羰基的结构类似物α-葎草烯完全没有活性。除了诱导性NF-κB外，组成型活性NF-κB也受到抑制。姜酮醇对NF-κB的抑制作用与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关。姜酮醇还抑制由TNF、TNFR1、TRADD、TRAF2、NIK和IKK激活的NF-κB依赖性报告基因表达，但不抑制由NF-κB的p65亚基激活的报告基因表达。NF-κB调控的基因产物，如细胞周期蛋白D1、COX-2、MMP-9、ICAM-1、c-Myc、生存素、IAP1、IAP2、XIAP、Bcl-2、Bcl-xL、Bfl-1/A1、TRAF1和FLIP，均被姜酮醇下调。这种下调导致细胞因子和化疗药物诱导的凋亡增强。姜酮醇对这些NF-κB调控基因表达的抑制作用也与TNF诱导的侵袭活性抑制相关。总体而言，我们的结果表明姜酮醇抑制致癌物诱导的NF-κB激活和NF-κB调控的基因表达，这种抑制作用可能为姜酮醇预防和治疗癌症提供分子基础。
