Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48201, USA.
Toxicol Sci. 2012 Oct;129(2):363-71. doi: 10.1093/toxsci/kfs199. Epub 2012 Jun 13.
Environmental exposure to arsenic, especially the trivalent inorganic form (As(3+)), 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 As(3+)-induced Akt activation in human bronchial epithelial cells. As(3+) 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 As(3+)-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 As(3+) treatment. Taken together, these data revealed a new signaling mechanism that might be pivotal in As(3+)-induced malignant transformation of the cells by linking the key stress signaling pathway, JNK, to the activation of Stat3 and the carcinogenic kinase, Akt.
环境砷暴露，特别是三价无机砷（As(3+)），除了一些其他疾病如皮肤损伤、心血管疾病、神经病变和内脏器官损伤外，还与人类癌症有关。在本研究中，我们描述了 c-Jun NH2 激酶（JNK）和信号转导和转录激活因子 3（Stat3）的新信号轴及其在人支气管上皮细胞中 As(3+)诱导 Akt 激活中的作用。As(3+)以剂量和时间依赖的方式激活 JNK 并诱导 Stat3 在丝氨酸 727（S727）处磷酸化，这与 Akt 激活同时发生。通过 JNK 抑制剂 SP600125 处理、JNK 的 siRNA 敲低或 JNK1 或 JNK2 基因的遗传缺陷破坏 JNK 信号通路，可消除 As(3+)诱导的 Stat3 的 S727 磷酸化、Akt 激活以及随后的血管内皮生长因子（VEGF）释放和细胞迁移。类似地，用 Stat3 抑制剂或 Stat3 siRNA 预处理细胞可防止 Akt 激活和 VEGF 从细胞中释放，以响应 As(3+)处理。总之，这些数据揭示了一种新的信号机制，该机制可能通过将关键应激信号通路 JNK 与 Stat3 和致癌激酶 Akt 的激活联系起来，在 As(3+)诱导的细胞恶性转化中起关键作用。
