JNK-Dependent Stat3 Phosphorylation Contributes to Akt Activation in Response to Arsenic Exposure
JNK-Dependent Stat3 Phosphorylation Contributes to Akt Activation in Response to Arsenic Exposure
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DOI：
10.1093/toxsci/kfs199
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发表时间：
2012-10-01
影响因子：
3.8
通讯作者：
Chen, Fei
中科院分区：
文献类型：
--
作者：
Liu, Jia;Chen, Bailing;Chen, Fei
环境暴露于砷，特别是三价无机形式（As 3+），已与人类癌症以及许多其他疾病，包括皮肤病变，心血管疾病，神经病和内脏器官损伤。在本研究中，我们描述了一种新的信号转导轴的c-Jun NH 2激酶（JNK）和信号转导和转录激活因子3（Stat 3）和其参与As 3+诱导的Akt激活人支气管上皮细胞。As 3+以剂量和时间依赖性方式激活JNK并诱导Stat 3在丝氨酸727（S727）处的磷酸化，这与Akt激活同时发生。JNK抑制剂SP 600125、JNK的siRNA敲低或JNK 1或JNK 2基因的遗传缺陷处理的JNK信号通路的破坏废除了As 3+诱导的Stat 3的S727磷酸化、Akt活化以及随后的血管内皮生长因子（VEGF）的释放和细胞的迁移。类似地，用Stat 3抑制剂或Stat 3 siRNA预处理细胞阻止Akt活化和响应于As 3+处理的VEGF从细胞释放。总之，这些数据揭示了一个新的信号转导机制，这可能是关键的As 3+诱导的恶性转化的细胞连接的关键应激信号通路，JNK，激活Stat 3和致癌激酶，Akt。
Environmental exposure to arsenic, especially the trivalent inorganic form (As3+), has been linked to human cancers in addition to a number of other diseases including skin lesions, cardiovascular disorders, neuropathy, and internal organ injury. In the present study, we describe a novel signaling axis of the c-Jun NH2 kinase (JNK) and signal transducer and activator of transcription 3 (Stat3) and its involvement in As3+-induced Akt activation in human bronchial epithelial cells. As3+ activates JNK and induces phosphorylation of the Stat3 at serine 727 (S727) in a dose- and time-dependent manner, which occurred concomitantly with Akt activation. Disruption of the JNK signaling pathway by treatment with the JNK inhibitor SP600125, siRNA knockdown of JNK, or genetic deficiency of the JNK1 or JNK2 gene abrogated As3+-induced S727 phosphorylation of Stat3, Akt activation, and the consequent release of vascular endothelial growth factor (VEGF) and migration of the cells. Similarly, pretreatment of the cells with Stat3 inhibitor or Stat3 siRNA prevented Akt activation and VEGF release from the cells in response to As3+ treatment. Taken together, these data revealed a new signaling mechanism that might be pivotal in As3+-induced malignant transformation of the cells by linking the key stress signaling pathway, JNK, to the activation of Stat3 and the carcinogenic kinase, Akt.