Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells
Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells
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吴茱萸碱通过诱导肝细胞癌细胞中的磷酸酶 shatterproof 1 抑制 STAT3 信号传导。
DOI：
10.1016/j.canlet.2012.09.019
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发表时间：
2013-01-28
期刊：
影响因子：
9.7
通讯作者：
Cao, Peng
中科院分区：
文献类型：
--
作者：
Yang, Jie;Cai, Xueting;Cao, Peng
信号转导和转录激活因子3（STAT 3）的激活与肝癌细胞的存活、增殖、血管生成和免疫抑制有关。能够抑制STAT 3活化的药剂具有成为癌症治疗剂的潜力。本研究旨在探讨吴茱萸碱在体外对STAT 3通路的抑制作用及在体内对肝癌细胞的抗肿瘤作用。我们发现，吴茱萸碱抑制组成和白细胞介素-6（IL-6）诱导的STAT 3酪氨酸705（Tyr（705））的激活有效。吴茱萸碱还抑制Janus激活激酶2（JAK 2）、Src和细胞外调节蛋白激酶1/2（ERK 1/2）的磷酸化。有趣的是，用过钒酸钠处理细胞消除了吴茱萸碱对IL-6诱导的STAT 3（Tyr（705））活化的抑制，表明蛋白酪氨酸磷酸酶的参与。事实上，进一步的研究表明，吴茱萸碱诱导磷酸酶防碎1（SHP-1）的表达。小干扰RNA抑制SHP-1基因表达后，吴茱萸碱抑制IL-6诱导的STAT 3（Tyr（705））活化的能力消失。吴茱萸碱还抑制STAT 3 DNA结合活性，下调STAT 3介导的基因的表达，导致增殖抑制，诱导细胞凋亡和细胞周期阻滞。在体内，吴茱萸碱显着抑制肿瘤生长的皮下异种移植模型与HepG 2细胞。总之，吴茱萸碱通过诱导SHP-1阻断STAT 3信号通路，在体内外均表现出抗肿瘤作用。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
The activation of signal transducer and activator of transcription signaling 3 (STAT3) has been linked with the survival, proliferation, angiogenesis and immunosuppression of hepatocellular carcinoma cells (HCCs). Agents that can suppress STAT3 activation have potential to be cancer therapeutics. In this study, we investigated the inhibitory effect of evodiamine on STAT3 pathway in vitro and the anti-tumor effect of evodiamine in vivo in HCC. We found that evodiamine suppressed both constitutive and interleukin-6 (IL-6)-induced activation of STAT3 tyrosine 705 (Tyr(705)) effectively. The phosphorylation of Janus-activated kinase 2 (JAK2), Src and extracellular regulated protein kinases 1/2 (ERK1/2) were also suppressed by evodiamine. Interestingly, treatment of cells with sodium pervanadate abrogated the inhibition of evodiamine on IL-6-induced STAT3 (Tyr(705)) activation indicating the involvement of protein tyrosine phosphatases. Indeed, further studies demonstrated that evodiamine induced the expression of phosphatase shatterproof 1 (SHP-1). Moreover, inhibition of SHP-1 gene by small interference RNA abolished the ability of evodiamine to inhibit IL-6-induced STAT3 (Tyr(705)) activation. Evodiamine also suppressed STAT3 DNA binding activity and down-regulated the expression of STAT3-mediated genes leading to the suppression of proliferation, induction of cell apoptosis and cell cycle arrest. In vivo, evodiamine significantly inhibited tumor growth in a subcutaneous xenograft model with HepG2 cells. In summary, evodiamine blocked STAT3 signaling pathway by inducing SHP-1 and exhibited anticancer effect in vitro and in vivo. (C) 2012 Elsevier Ireland Ltd. All rights reserved.