Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis
Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis
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冬凌草甲素触发 Fbw7 介导的 c-Myc 蛋白酶体降解诱导细胞生长抑制和细胞凋亡
DOI：
10.1158/1535-7163.mct-12-0066
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发表时间：
2012-05-01
影响因子：
5.7
通讯作者：
Qu, Liang-Hu
中科院分区：
文献类型：
--
作者：
Huang, Hui-Lin;Weng, Heng-You;Qu, Liang-Hu
转录因子c-Myc在细胞命运决定中很重要，并且经常在癌细胞中过表达，使其成为有吸引力的治疗靶点。天然化合物是目前针对c-Myc的策略之一，但它们的作用模式仍需要表征。为了探索天然二萜类化合物冬凌草甲素的抗癌活性的机制，我们进行了miRNA表达谱和统计分析，强烈表明c-Myc是冬凌草甲素的潜在分子靶点。此外，实验数据表明，冬凌草甲素显着降低c-Myc蛋白水平在体外和体内，这种减少是由泛素-蛋白酶体系统介导的。Fbw 7是泛素-蛋白酶体系统的一个组成部分，也是c-Myc的E3泛素连接酶，在K562细胞和其他白血病和淋巴瘤细胞中迅速上调，导致c-Myc的快速周转。在Fbw 7的WD结构域中含有突变的细胞系中，在短期治疗期间，由冬凌草甲素诱导的c-Myc的降解被减弱。冬凌草甲素也能激活GSK-3（一种Fbw 7引发激酶），沿着T58磷酸化c-Myc的增加。此外，敲低Fbw 7或强制表达稳定的c-Myc导致对冬凌草甲素诱导的细胞凋亡的敏感性降低。我们的观察有助于阐明冬凌草甲素的抗癌机制，并阐明这种天然化合物作为Fbw 7-c-Myc通路靶向剂在癌症治疗中的应用。Mol Cancer Ther; 11（5）; 1155-65.©2012 AACR。
The transcription factor c-Myc is important in cell fate decisions and is frequently overexpressed in cancer cells, making it an attractive therapeutic target. Natural compounds are among the current strategies aimed at targeting c-Myc, but their modes of action still need to be characterized. To explore the mechanisms underlying the anticancer activity of a natural diterpenoid, oridonin, we conducted miRNA expression profiling and statistical analyses that strongly suggested that c-Myc was a potential molecular target of oridonin. Furthermore, experimental data showed that oridonin significantly reduced c-Myc protein levels in vitro and in vivo and that this reduction was mediated by the ubiquitin-proteasome system. Fbw7, a component of the ubiquitin-proteasome system and an E3 ubiquitin ligase of c-Myc, was upregulated rapidly in K562 cells and other leukemia and lymphoma cells, resulting in the rapid turnover of c-Myc. In cell lines harboring mutations in the WD domain of Fbw7, the degradation of c-Myc induced by oridonin was attenuated during short-term treatment. GSK-3, an Fbw7 priming kinase, was also activated by oridonin, along with an increase in T58-phosphorylated c-Myc. Furthermore, the knockdown of Fbw7 or the forced expression of stable c-Myc resulted in reduced sensitization to oridonin-induced apoptosis. Our observations help to clarify the anticancer mechanisms of oridonin and shed light on the application of this natural compound as an Fbw7-c-Myc pathway targeting agent in cancer treatment. Mol Cancer Ther; 11(5); 1155–65. ©2012 AACR.