The mechanism of apoptosis induced by a novel thioredoxin reductase inhibitor in A549 cells:: Possible involvement of nuclear factor-κB-dependent pathway
The mechanism of apoptosis induced by a novel thioredoxin reductase inhibitor in A549 cells:: Possible involvement of nuclear factor-κB-dependent pathway
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DOI：
10.1016/j.ejphar.2006.10.037
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发表时间：
2007-01-26
影响因子：
5
通讯作者：
Zeng, Huihui
中科院分区：
文献类型：
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作者：
Lan, Linxiang;Zhao, Fang;Zeng, Huihui
1，2-[bis(1，2-benzisoselenazolone-3(2H)-ketone)]ethane(BBSKE，PCT：CN02/00412)是本实验室合成的一种新型硫氧还蛋白还原酶抑制剂，已被证明能抑制多种人类癌细胞的生长并诱导其凋亡。本文报道了BBSKE诱导A549细胞凋亡的可能分子机制。BBSKE可降低Bcl2、Bclxl、Proaspase-9和Proaspase-3的蛋白水平，并以剂量依赖的方式使细胞色素C从线粒体释放到胞浆中，提示线粒体依赖的细胞凋亡的发生。通过凝胶迁移率改变分析(EMSA)发现，经BBSKE处理后，核因子-kappa B的DNA结合活性减弱，同时免疫共沉淀实验中硫氧还蛋白与核因子-kappaB的免疫共沉淀物减少。同时，Western分析和免疫细胞化学检测显示，BBSKE对PI-kappa B-α/I-kappa B-α的比值以及p65在胞浆和胞核之间的亚细胞定位没有明显改变。此外，BBSKE治疗后，NF-kappa B调控的抗细胞凋亡基因Bcl2、Bclxl、CIAP-2和XIAP的mRNA水平呈剂量依赖性降低。以上结果提示，BBSKE可能通过抑制硫氧还蛋白还原酶-硫氧还蛋白-核因子-kappa B途径诱导A549细胞发生线粒体依赖性的凋亡。(C)2006爱思唯尔B.V.保留所有权利。
1,2-[bis(1,2-benzisoselenazolone-3(2H)-ketone)]ethane (BBSKE, PCT: CN02/00412), a novel thioredoxin reductase inhibitor previously synthesized in our lab, has been demonstrated to inhibit the growth of a variety of human cancer cells and to induce apoptosis. Here we report on the potential molecular mechanism of apoptosis induced by BBSKE in A549 cells. The treatment of BBSKE reduced the protein levels of Bcl-2, Bcl-xL, procaspase-9 and procaspase-3, and caused the release of cytochrome C from the mitochondria to the cytosol in a dose-dependent manner, suggesting the onset of mitochondria-dependent apoptosis. Through electrophoretic mobility shift assay (EMSA), the DNA-binding activity of nuclear factor-kappa B (NF-kappa B) was found to be attenuated after BBSKE treatment, accompanied by the diminution of the immunoprecipitated complex of thioredoxin and NF-kappa B in co-immunoprecipitation experiments. Meanwhile, the ratio of pI kappa B-alpha to I kappa B-alpha and the subcellular localization of p65 between cytoplasm and nucleus were not significantly altered by BBSKE treatment, as demonstrated in western analysis and immunocytochemistry assay. Furthermore, the mRNA levels of the NF-kappa B regulated anti-apoptosis genes Bcl-2, Bcl-xL, cIAP-2 and XIAP were decreased in a dose-dependent manner after BBSKE treatment. All the above observations suggest that BBSKE induce rnitochondria-dependent apoptosis in A549 cells probably through suppressing the thioredoxin reductase-thioredoxin-NF-kappa B pathway. (c) 2006 Elsevier B.V. All rights reserved.