Pandey Manoj K, Sung Bokyung, Ahn Kwang Seok, Kunnumakkara Ajaikumar B, Chaturvedi Madan M, Aggarwal Bharat B
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Blood. 2007 Nov 15;110(10):3517-25. doi: 10.1182/blood-2007-03-079616. Epub 2007 Aug 2.
Gambogic acid (GA), a xanthone derived from the resin of the Garcinia hanburyi, has been recently demonstrated to bind transferrin receptor and exhibit potential anticancer effects through a signaling mechanism that is not fully understood. Because of the critical role of NF-kappaB signaling pathway, we investigated the effects of GA on NF-kappaB-mediated cellular responses and NF-kappaB-regulated gene products in human leukemia cancer cells. Treatment of cells with GA enhanced apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, inhibited the expression of gene products involved in antiapoptosis (IAP1 and IAP2, Bcl-2, Bcl-x(L), and TRAF1), proliferation (cyclin D1 and c-Myc), invasion (COX-2 and MMP-9), and angiogenesis (VEGF), all of which are known to be regulated by NF-kappaB. GA suppressed NF-kappaB activation induced by various inflammatory agents and carcinogens and this, accompanied by the inhibition of TAK1/TAB1-mediated IKK activation, inhibited IkappaBalpha phosphorylation and degradation, suppressed p65 phosphorylation and nuclear translocation, and finally abrogated NF-kappaB-dependent reporter gene expression. The NF-kappaB activation induced by TNFR1, TRADD, TRAF2, NIK, TAK1/TAB1, and IKKbeta was also inhibited. The effect of GA mediated through transferrin receptor as down-regulation of the receptor by RNA interference reversed its effects on NF-kappaB and apoptosis. Overall our results demonstrate that GA inhibits NF-kappaB signaling pathway and potentiates apoptosis through its interaction with the transferrin receptor.
藤黄酸（GA）是一种从藤黄树脂中提取的氧杂蒽酮，最近研究表明它能与转铁蛋白受体结合，并通过一种尚未完全了解的信号传导机制发挥潜在的抗癌作用。由于核因子κB（NF-κB）信号通路的关键作用，我们研究了GA对人白血病癌细胞中NF-κB介导的细胞反应及NF-κB调控的基因产物的影响。用GA处理细胞可增强肿瘤坏死因子（TNF）和化疗药物诱导的细胞凋亡，抑制抗凋亡相关基因产物（IAP1和IAP2、Bcl-2、Bcl-x(L)和TRAF1）、增殖相关基因产物（细胞周期蛋白D1和c-Myc）、侵袭相关基因产物（COX-2和MMP-9）以及血管生成相关基因产物（VEGF）的表达，这些基因产物均已知受NF-κB调控。GA可抑制多种炎症因子和致癌物诱导的NF-κB激活，同时抑制TAK1/TAB1介导的IKK激活，抑制IκBα磷酸化和降解，抑制p65磷酸化和核转位，最终消除NF-κB依赖的报告基因表达。TNFR1、TRADD、TRAF2、NIK、TAK1/TAB1和IKKβ诱导的NF-κB激活也受到抑制。通过RNA干扰下调转铁蛋白受体介导的GA效应可逆转其对NF-κB和细胞凋亡的影响。总体而言，我们的结果表明GA通过与转铁蛋白受体相互作用抑制NF-κB信号通路并增强细胞凋亡。
