MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy
MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy
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DOI：
10.1128/mcb.02364-06
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发表时间：
2007-06-01
影响因子：
5.3
通讯作者：
Ecsedy, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Hoar, Kara;Chakravarty, Arijit;Ecsedy, Jeffrey A.
Aurora A激酶在有丝分裂纺锤体的正确组装和功能中起着至关重要的作用，因为它的扰动会导致中心体分离、纺锤体极组织和染色体聚集的缺陷。此外，Aurora A的破坏通过一种涉及非整倍体产生的机制导致细胞死亡。然而，Aurora A抑制的直接功能后果与非整倍体的发展之间的联系还没有明确的定义。在这项研究中，我们描述了使用选择性Aurora A小分子抑制剂MLN8054抑制Aurora A后导致非整倍体的一系列事件。用MLN8054处理的人肿瘤细胞显示异常有丝分裂纺锤体的发生率很高，通常带有未分离的中心体。尽管这些纺锤体缺陷导致有丝分裂延迟，但细胞最终以接近未处理细胞的频率分裂。我们发现，分裂细胞中的许多纺锤体是两极的，尽管它们在一个或多个纺锤体极处缺乏中心体。MLN8054处理的细胞在中期经常出现排列缺陷，在后期出现染色体标记，在末期出现染色质桥。与染色体分离缺陷一致的是，MLN8054处理的细胞随着时间的推移发展成非整倍体。综上所述，这些结果表明，Aurora A抑制通过发展有害的非整倍体来杀死肿瘤细胞。
Aurora A kinase plays an essential role in the proper assembly and function of the mitotic spindle, as its perturbation causes defects in centrosome separation, spindle pole organization, and chromosome congression. Moreover, Aurora A disruption leads to cell death via a mechanism that involves aneuploidy generation. However, the link between the immediate functional consequences of Aurora A inhibition and the development of aneuploidy is not clearly defined. In this study, we delineate the sequence of events that lead to aneuploidy following Aurora A inhibition using MLN8054, a selective Aurora A small-molecule inhibitor. Human tumor cells treated with MLN8054 show a high incidence of abnormal mitotic spindles, often with unseparated centrosomes. Although these spindle defects result in mitotic delays, cells ultimately divide at a frequency near that of untreated cells. We show that many of the spindles in the dividing cells are bipolar, although they lack centrosomes at one or more spindle poles. MLN8054-treated cells frequently show alignment defects during metaphase, tagging chromosomes in anaphase, and chromatin bridges during telophase. Consistent with the chromosome segregation defects, cells treated with MLN8054 develop aneuploidy over time. Taken together, these results suggest that Aurora A inhibition kills tumor cells through the development of deleterious aneuploidy.