Mitotic entry: Non-genetic heterogeneity exposes the requirement for Plk1.
Mitotic entry: Non-genetic heterogeneity exposes the requirement for Plk1.
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DOI：
10.18632/oncotarget.5507
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发表时间：
2015-11-03
期刊：
影响因子：
--
通讯作者：
Taylor SS
中科院分区：
文献类型：
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作者：
Aspinall CF;Zheleva D;Tighe A;Taylor SS
寻求开发新的抗有丝分裂化疗药物已经导致了几种靶向Plk 1的小分子抑制剂的产生，Plk 1是细胞分裂多个方面所需的蛋白激酶。先前的研究表明，暴露于Plk1抑制剂后，细胞进入有丝分裂，在前期短暂延迟，然后由于无法进行中心体分离而停止有丝分裂。在这里，我们表明，四种不同类型的Plk1抑制剂阻断有丝分裂进入几种癌细胞系和非转化RPE-1细胞。停滞在G2期的细胞比例是细胞系和浓度依赖性的，并且受到非遗传异质性的影响。抑制剂洗脱后，G2阻滞减轻，细胞进入有丝分裂，但随后无法完成细胞分裂，表明大多数Plk1抑制剂不完全可逆。一个例外是CYC140844;与本文研究的其他五种抑制剂相比，这种新型Plk1抑制剂是完全可逆的。我们讨论了开发Plk1抑制剂作为化疗药物和研究工具的影响。
The quest to develop novel antimitotic chemotherapy agents has led to the generation of several small molecule inhibitors targeting Plk1, a protein kinase required for multiple aspects of cell division. Previous studies have shown that upon exposure to Plk1 inhibitors, cells enter mitosis, delay briefly in prophase and then arrest in mitosis due to an inability to undergo centrosome separation. Here, we show that four different classes of Plk1 inhibitor block mitotic entry in several cancer cell lines and non-transformed RPE-1 cells. The proportion of cells that arrest in G2 is cell line and concentration dependent, and is subject to non-genetic heterogeneity. Following inhibitor washout, the G2 block is alleviated and cells enter mitosis but then fail to complete cell division indicating that most Plk1 inhibitors are not fully reversible. An exception is CYC140844; in contrast to five other inhibitors examined here, this novel Plk1 inhibitor is fully reversible. We discuss the implications for developing Plk1 inhibitors as chemotherapy agents and research tools.