IKKβ downregulation is critical for triggering JNKs-dependent cell apoptotic response in the human hepatoma cells under arsenite exposure
IKKβ downregulation is critical for triggering JNKs-dependent cell apoptotic response in the human hepatoma cells under arsenite exposure
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DOI：
10.1007/s11010-011-0921-3
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发表时间：
2011-12-01
影响因子：
4.3
通讯作者：
Song, Lun
中科院分区：
文献类型：
--
作者：
Li, Yi;Hao, Yi;Song, Lun
亚砷酸盐在治疗白血病方面有着悠久的历史，在其他癌症的治疗中也可能有效。我们以前发表的数据表明，砷暴露通过激活JNKs/AP-1通路诱导HepG 2人肝癌细胞凋亡，但JNKs（c-Jun N-terminal kinase）级联激活的上游信号事件尚未完全发现。由于应激条件下IKK/NF-κ B和JNKs通路之间的相互作用是一个热门话题，在这篇文章中，我们研究了IKK复合物的催化亚基IKK α和IKK β在亚砷酸钠诱导的HepG 2细胞JNKs通路活化中的潜在作用。我们发现，砷暴露诱导JNKs和AP-1激活伴随着IKK α和IKK β表达的显着减少。IKK β的过表达，而不是IKK α的过表达，抑制亚砷酸盐诱导的MKK 7/JNKs/AP-1通路活化以及凋亡反应。因此，我们得出结论，IKK β表达的下调是介导JNK通路激活和细胞凋亡反应在砷暴露的HepG 2细胞的先决条件的信号事件。以IKK β为靶点可能有助于提高亚砷酸盐的肿瘤治疗效果。
Arsenite has a long history in treating leukemia, which might be also effective in the therapy of other cancers. Our previous published data have demonstrated that arsenite exposure induces apoptosis in the HepG2 human hepatoma cells via activating JNKs/AP-1 pathway, but the upstream signaling events responsible for JNKs (c-Jun N-terminal kinase) cascade activation have not been fully discovered. Since cross-talk between IKK/NF-kappa B and JNKs pathways under stress conditions is a hot topic, in this article, we investigate the potential roles of IKK alpha and IKK beta, the catalytic subunits of IKK complexes, in the arsenite-induced JNKs pathway activation in the HepG2 cells. We found that arsenite exposure induced JNKs and AP-1 activation accompanying with a significant reduction of both IKK alpha and IKK beta expressions. Overexpression of IKK beta, but not of IKK alpha, inhibited arsenite-induced MKK7/JNKs/AP-1 pathway activation as well as the apoptotic response. Therefore, we conclude that the downregulation of IKK beta expression is the prerequisite signaling event for mediating JNKs pathway activation and the cellular apoptotic response in the HepG2 cells under arsenite exposure. Targeting IKK beta might be helpful to enhance the tumor therapeutic effect of arsenite.