Xanthatin inhibits STAT3 and NF-κB signalling by covalently binding to JAK and IKK kinases
Xanthatin inhibits STAT3 and NF-κB signalling by covalently binding to JAK and IKK kinases
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黄黄素通过与 JAK 和 IKK 激酶共价结合抑制 STAT3 和 NF-kappa B 信号传导
DOI：
10.1111/jcmm.14322
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发表时间：
2019-06-01
影响因子：
5.3
通讯作者：
Yu, Qiang
中科院分区：
文献类型：
--
作者：
Liu, Man;Xiao, Cheng-qian;Yu, Qiang
信号转导和转录激活因子3(STAT3)和核因子-kappaB(NF-kappa B)信号通路的异常激活与癌症和炎症性疾病的发生发展有关。JAKS和IKKS分别是STAT3和NF-kappa B信号通路中的关键调节因子。因此，这两个激酶家族一直是开发药物来调节这两个信号通路的主要靶点。在这里，我们报道了一种从传统中草药苍耳子中提取的天然化合物黄原素，它是STAT3和NF-kappa B信号通路的有效抑制剂。我们的数据表明，黄素是一种共价抑制剂，其活性依赖于其α-亚甲基-伽马-丁内酯基团。它优先与JAK2的Cys243和IKKβ的Cys412和Cys464相互作用，使其失活。在这样做的过程中，黄原素优先抑制了具有结构性激活的STAT3和P65的癌细胞株的生长。这些数据表明，黄原素可能是一种很有前途的抗癌抗炎药物候选药物。
Aberrant activation of the signal transducer and activator of transcription 3 (STAT3) and the nuclear factor-kappa B (NF-kappa B) signalling pathways is associated with the development of cancer and inflammatory diseases. JAKs and IKKs are the key regulators in the STAT3 and NF-kappa B signalling respectively. Therefore, the two families of kinases have been the major targets for developing drugs to regulate the two signalling pathways. Here, we report a natural compound xanthatin from the traditional Chinese medicinal herb Xanthium L. as a potent inhibitor of both STAT3 and NF-kappa B signalling pathways. Our data demonstrated that xanthatin was a covalent inhibitor and its activities depended on its alpha-methylene-gamma-butyrolactone group. It preferentially interacted with the Cys243 of JAK2 and the Cys412 and Cys464 of IKK beta to inactivate their activities. In doing so, xanthatin preferentially inhibited the growth of cancer cell lines that have constitutively activated STAT3 and p65. These data suggest that xanthatin may be a promising anticancer and anti-inflammation drug candidate.