17-Hydroxy-jolkinolide B Inhibits Signal Transducers and Activators of Transcription 3 Signaling by Covalently Cross-Linking Janus Kinases and Induces Apoptosis of Human Cancer Cells
17-Hydroxy-jolkinolide B Inhibits Signal Transducers and Activators of Transcription 3 Signaling by Covalently Cross-Linking Janus Kinases and Induces Apoptosis of Human Cancer Cells
复制标题
17-羟基-jolkinolide B 通过共价交联 Janus 激酶抑制转录 3 信号转导的信号转导子和激活子，并诱导人类癌细胞凋亡。
DOI：
10.1158/0008-5472.can-09-0462
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发表时间：
2009-09-15
期刊：
影响因子：
11.2
通讯作者：
Yu, Qiang
中科院分区：
文献类型：
--
作者：
Wang, Ying;Ma, Xiuquan;Yu, Qiang
Janus 激酶 (JAK)/信号转导子和转录激活子 (STAT) 通路的组成性激活在癌细胞中频繁发生，并有助于肿瘤发生。在STAT家族成员中，STAT3在人类肿瘤的发生和发展中发挥着关键作用。 STAT3介导的信号通路已被认为是一个有前途的抗癌靶点。在这里，我们发现 17-Hydroxy-jolkinolide B (HJB) 是一种来自中草药大戟 (Euphorbia fischeriana Steud) 的二萜类化合物，可强烈抑制白细胞介素 (IL)-6 诱导的以及组成型 STAT3 的激活。此外，我们发现 HJB 通过交联诱导 JAK 二聚化，直接靶向 JAK 家族激酶 JAK1、JAK2 和 TYK2。添加 DTT 或谷胱甘肽可防止 JAK 交联并阻断 HJB 对 IL-6 诱导的 STAT3 激活的抑制作用，表明 HJB 可能与 JAK 的半胱氨酸残基反应形成共价键，从而使 JAK 失活。液相色谱/质谱分析证实每个 HJB 与两种硫醇反应。 HJB 对 JAK/STAT3 通路的影响是特异的，因为 HJB 对血小板衍生生长因子、表皮生长因子或胰岛素样生长因子 I 信号通路没有影响。最后，我们发现 HJB 抑制肿瘤细胞的生长并诱导其凋亡，特别是那些具有组成型激活的 STAT3 的肿瘤细胞。我们认为天然化合物 HJB 作为有效的 STAT3 信号传导抑制剂是一种有前途的抗癌药物候选物。
Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway occurs frequently in cancer cells and contributes to oncogenesis. Among the members of STAT family, STAT3 plays a pivotal role in the development and progression of human tumors. The STAT3-mediated signaling pathway has been recognized as a promising anticancer target. Here, we show that 17-Hydroxy-jolkinolide B (HJB), a diterpenoid from the Chinese medicinal herb Euphorbia fischeriana Steud, strongly inhibits interleukin (IL)-6-induced as well as constitutive STAT3 activation. Furthermore, we show that HJB directly targets the JAK family kinases, JAK1, JAK2, and TYK2, by inducing dimerization of the JAKs via cross-linking. Addition of DTT or glutathione prevents the JAK cross-linking and blocks the inhibitory effects of HJB on IL-6-induced STAT3 activation, suggesting that HJB may react with cystein residues of JAKs to form covalent bonds that inactivate JAKs. Liquid chromatography/mass spectrometry analysis confirmed that each HJB reacted with two thiols. The effect of HJB on the JAK/STAT3 pathway is specific as HJB has no effect on platelet-derived growth factor, epidermal growth factor, or insulin-like growth factor I signaling pathways. Finally, we show that HJB inhibits growth and induces apoptosis of tumor cells, particularly those tumor cells with constitutively activated STAT3. We propose that the natural compound HJB is a promising anticancer drug candidate as a potent STAT3 signaling inhibitor.