Modification of cysteine residue in p65 subunit of nuclear factor-kappaB (NF-kappaB) by picroliv suppresses NF-kappaB-regulated gene products and potentiates apoptosis.
Modification of cysteine residue in p65 subunit of nuclear factor-kappaB (NF-kappaB) by picroliv suppresses NF-kappaB-regulated gene products and potentiates apoptosis.
复制标题
通过Picroliv抑制NF-kappab调节的基因产物并增强细胞凋亡的核因子-kappab（NF-kappab）p65亚基（NF-kappab）的修饰。
DOI：
10.1158/0008-5472.can-08-1902
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发表时间：
2008-11-01
期刊：
影响因子：
11.2
通讯作者：
Aggarwal BB
中科院分区：
文献类型：
--
作者：
Anand P;Kunnumakkara AB;Harikumar KB;Ahn KS;Badmaev V;Aggarwal BB
Picroliv是一种来自植物胡黄连的环烯醚萜苷，传统上用于治疗发烧，哮喘，肝炎和其他炎症。然而，其治疗作用的确切机制仍然未知。由于NF-κB活化在炎症和癌变中起主要作用，因此我们假设picroliv必须通过抑制NF-κB介导的信号级联活化来干扰该途径。电泳迁移率变动分析显示picroliv预处理可阻断TNF诱导的NF-κB活化。该糖苷还抑制由致癌剂和炎症剂如CSC、PMA、OA、H2 O2、LPS和EGF激活的NF-κB。当检查作用机制时，我们发现picroliv抑制IκBα激酶的活化，导致IκBα磷酸化和降解的抑制。它还抑制p65的磷酸化和核转位。进一步的研究表明，picroliv直接抑制p65与DNA的结合，而用还原剂处理可逆转这种结合，表明半胱氨酸残基在与picroliv相互作用中的作用。p65中半胱氨酸残基38突变为丝氨酸消除了picroliv的这种作用。picroliv对NF-κ B的抑制导致NF-κ B调节蛋白的抑制，包括与细胞存活（IAP 1、Bcl-2、Bcl-xL、生存素和TRAF 2）、增殖（细胞周期蛋白D1和考克斯-2）、血管生成（VEGF）和侵袭（ICAM-1和MMP-9）相关的蛋白。抑制这些蛋白，增强TNF诱导的细胞凋亡。总之，我们的结果表明，picroliv抑制NF-κB活化途径，这可能解释其抗炎和抗癌作用。
Picroliv, an iridoid glycoside derived from the plant Picrorhiza kurroa, is used traditionally to treat fever, asthma, hepatitis and other inflammatory conditions. However, the exact mechanism of its therapeutic action is still unknown. Because NF-κB activation plays a major role in inflammation and carcinogenesis, we postulated that picroliv must interfere with this pathway by inhibiting the activation of NF-κB mediated signal cascade. Electrophoretic mobility shift assay showed that pretreatment with picroliv abrogated TNF induced activation of NF-κB. The glycoside also inhibited NF-κB activated by carcinogenic and inflammatory agents such as CSC, PMA, OA, H2O2, LPS and EGF. When examined for the mechanism of action, we found that picroliv inhibited activation of IκBα kinase, leading to inhibition of phosphorylation and degradation of IκBα. It also inhibited phosphorylation and nuclear translocation of p65. Further studies revealed that picroliv directly inhibits the binding of p65 to DNA, which was reversed by the treatment with reducing agents, suggesting a role for a cysteine residue in interaction with picroliv. Mutation of cysteine residue 38 in p65 to serine abolished this effect of picroliv. NF-κB inhibition by picroliv lead to suppression of NF-κB-regulated proteins, including those linked with cell survival (IAP1, Bcl-2, Bcl-xL, survivin, and TRAF2), proliferation (cyclin D1 and COX-2), angiogenesis (VEGF), and invasion (ICAM-1 and MMP-9). Suppression of these proteins, enhanced apoptosis induced by TNF. Overall, our results demonstrate that picroliv inhibits the NF-κB activation pathway, which may explain its anti-inflammatory and anticarcinogenic effects.