Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest.
Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, PERIOD2-dependent growth arrest.
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DOI：
10.1186/gb-2008-9-6-r92
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发表时间：
2008
期刊：
影响因子：
12.3
通讯作者：
Stockwell BR
中科院分区：
文献类型：
--
作者：
Yang WS;Stockwell BR
酪蛋白激酶1 β被确定为开发选择性抗癌试剂的潜在靶点。激酶作为药物开发的靶点正在进行广泛的研究。发现新的激酶，其抑制诱导癌细胞选择性致死将是有价值的。RNA干扰的最新进展使这一目标得以实现。我们筛选了5,760个靶向人类激酶组的短发夹RNA克隆，以检测癌细胞比正常细胞更依赖的人类激酶。我们采用了两步筛选策略，使用人肉瘤细胞系和人成纤维细胞衍生的等基因细胞系，发现靶向CSNK 1 E（一种调节昼夜节律的时钟基因）的短发夹RNA可以诱导工程肿瘤细胞的选择性生长抑制。基因表达数据的分析显示，与非致瘤性正常组织相比，CSNK 1 E在几种癌组织样品中过表达，表明CSNK 1 E在新生或维持中具有积极作用。用IC 261（酪蛋白激酶1-ε（CK 1 ε）（CSNK 1 E的蛋白质产物）的激酶结构域抑制剂）处理，显示出类似程度的癌细胞选择性生长抑制作用。在寻找介导IC 261诱导的生长抑制的CK 1 ε底物时，我们发现敲除参与昼夜节律控制的另一个时钟基因PER 2可以挽救IC 261诱导的生长抑制。我们将CK 1 ε确定为开发具有高治疗指数的抗癌试剂的潜在靶点。这些数据支持了生物钟基因可以控制细胞周期和细胞存活信号的假设，并强调了CK 1 ε和PERIOD 2在连接这些系统中的核心作用。
Casein kinase 1 epsilon is identified as a potential target for developing selective anticancer reagents. Kinases are under extensive investigation as targets for drug development. Discovering novel kinases whose inhibition induces cancer-cell-selective lethality would be of value. Recent advances in RNA interference have enabled the realization of this goal. We screened 5,760 short hairpin RNA clones targeting the human kinome to detect human kinases on which cancer cells are more dependent than normal cells. We employed a two-step screening strategy using human sarcoma cell lines and human fibroblast-derived isogenic cell lines, and found that short hairpin RNAs targeting CSNK1E, a clock gene that regulates circadian rhythms, can induce selective growth inhibition in engineered tumor cells. Analysis of gene-expression data revealed that CSNK1E is overexpressed in several cancer tissue samples examined compared to non-tumorigenic normal tissue, suggesting a positive role of CSNK1E in neogenesis or maintenance. Treatment with IC261, a kinase domain inhibitor of casein kinase 1-epsilon (CK1ε), a protein product of CSNK1E, showed a similar degree of cancer-cell-selective growth inhibition. In a search for substrates of CK1ε that mediate IC261-induced growth inhibition, we discovered that knocking down PER2, another clock gene involved in circadian rhythm control, rescues IC261-induced growth inhibition. We identified CK1ε as a potential target for developing anticancer reagents with a high therapeutic index. These data support the hypothesis that circadian clock genes can control the cell cycle and cell survival signaling, and emphasize a central role of CK1ε and PERIOD2 in linking these systems.
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影响因子：
5.3
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