Alantolactone induces cell apoptosis partially through down-regulation of testes-specific protease 50 expression
Alantolactone induces cell apoptosis partially through down-regulation of testes-specific protease 50 expression
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Alantolactone 部分通过下调睾丸特异性蛋白酶 50 表达来诱导细胞凋亡
DOI：
10.1016/j.toxlet.2013.11.002
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发表时间：
2014-01-30
影响因子：
3.5
通讯作者：
Li, Yu-Xin
中科院分区：
文献类型：
--
作者：
Mi, Xu-Guang;Song, Zhen-Bo;Li, Yu-Xin
睾丸特异性蛋白酶50 （Testes-specific protease 50, TSP50）在许多癌症活检中异常表达，在肿瘤发生中起着至关重要的作用，这使其成为潜在的癌症治疗靶点。在这里，我们构建了一个由TSP50基因启动子驱动的萤火虫荧光素酶报告子来筛选能够抑制TSP50表达的天然化合物。随后我们鉴定了倍半萜内酯alantolactone能有效抑制TSP50基因启动子活性，进一步的结果表明alantolactone在mRNA和蛋白水平上也能有效抑制TSP50基因的表达。此外，我们发现alantolactone可以在TSP50高表达的癌细胞中增加Bax/Bcl-2的比例，激活caspase-9和caspase-3，令人惊讶的是，在相同的细胞中，仅通过敲低TSP50基因表达也可以观察到相同的效果。此外，我们的研究结果表明，在这些癌细胞中，过表达TSP50降低了细胞对阿兰妥内酯诱导的凋亡的敏感性。综上所述，这些结果表明，alantolactone至少部分通过下调TSP50表达诱导线粒体依赖性细胞凋亡。2013爱思唯尔爱尔兰有限公司版权所有。
Testes-specific protease 50 (TSP50) is aberrantly expressed in many cancer biopsies and plays a crucial role in tumorigenesis, which make it a potential cancer therapeutic target for drug discovery. Here, we constructed a firefly luciferase reporter driven by the TSP50 gene promoter to screen natural compounds capable of inhibiting the expression of TSP50. Then we identified alantolactone, a sesquiterpene lactone, could efficiently inhibit the promoter activity of TSP50 gene, further results revealed that alantolactone also efficiently inhibited the expression of TSP50 in both mRNA and protein levels. Moreover, we found alantolactone could increase the ratio of Bax/Bcl-2, and activate caspase-9 and caspase-3 in the cancer cells with high expression of TSP50, surprisingly, the same effects can also be observed in the same cells just by knockdown of TSP50 gene expression. Furthermore, our results suggested that overexpression of TSP50 decreased the cell sensitivity to alantolactone-induced apoptosis in those cancer cells. Taken together, these results suggest that alantolactone induces mitochondrial-dependent apoptosis at least partially via down-regulation of TSP50 expression. (C) 2013 Elsevier Ireland Ltd. All rights reserved.