Impairing the maintenance of germinative cells in Echinococcus multilocularis by targeting Aurora kinase
Impairing the maintenance of germinative cells in Echinococcus multilocularis by targeting Aurora kinase
复制标题
通过靶向极光激酶损害多房棘球绦虫生殖细胞的维持
DOI：
10.1371/journal.pntd.0007425
复制
发表时间：
2019-05-01
影响因子：
3.8
通讯作者：
Wang, Yanhai
中科院分区：
文献类型：
--
作者：
Cheng, Zhe;Liu, Fan;Wang, Yanhai
研究背景多房棘球绦虫囊虫幼虫的瘤样生长导致人泡状棘球绦虫病，这是一种主要影响肝脏的严重疾病。萌发细胞是成体干细胞的群体，对幼虫的生长和寄主内寄生虫的发育至关重要。萌发细胞库的维持依赖于它们广泛的增殖和自我更新的能力，这需要准确地控制细胞分裂周期。针对细胞分裂进程的调节因子可能会损害萌发细胞群，导致寄生虫的生长受阻。方法/主要发现在这项研究中，我们描述了EmAURKA和EmAURKB的特征，它们与极光激酶的成员有很大的相似之处，极光激酶是重要的有丝分裂蛋白，在细胞分裂中发挥关键作用。我们的数据表明EmAURKA和EmAURKB在多房棘球藻的生殖细胞中有活跃的表达。低浓度的MLN8237(Aurora A和Aurora B的双重抑制剂)导致有丝分裂过程中萌发细胞的染色体缺陷，而高浓度的MLN8237则导致萌发细胞的胞质分裂失败，导致多核细胞。抑制极光酶的活性最终导致多房棘球绦虫的萌发细胞群枯竭，进而导致幼虫生长抑制。结论/意义我们的研究结果证实了极光激酶在多房棘球绦虫有丝分裂进程和生殖细胞维持中的重要作用，并提示极光激酶是开发新型抗人泡型包虫病化疗药物的有希望的药物靶点。
Background The tumor-like growth of the metacestode larvae of the tapeworm E. multilocularis causes human alveolar echinococcosis, a severe disease mainly affecting the liver. The germinative cells, a population of adult stem cells, are crucial for the larval growth and development of the parasite within the hosts. Maintenance of the germinative cell pools relies on their abilities of extensive proliferation and self-renewal, which requires accurate control of the cell division cycle. Targeting regulators of the cell division progression may impair germinative cell populations, leading to impeded parasite growth. Methodology/Principal findings In this study, we describe the characterization of EmAURKA and EmAURKB, which display significant similarity to the members of Aurora kinases that are essential mitotic kinases and play key roles in cell division. Our data suggest that EmAURKA and EmAURKB are actively expressed in the germinative cells of E. multilocularis. Treatment with low concentrations of MLN8237, a dual inhibitor of Aurora A and B, resulted in chromosomal defects in the germinative cells during mitosis, while higher concentrations of MLN8237 caused a failure in cytokinesis of the germinative cells, leading to multinucleated cells. Inhibition of the activities of Aurora kinases eventually resulted in depletion of the germinative cell populations in E. multilocularis, which in turn caused larval growth inhibition of the parasite. Conclusions/Significance Our data demonstrate the vital roles of Aurora kinases in the regulation of mitotic progression and maintenance of the germinative cells in E. multilocularis, and suggest Aurora kinases as promising druggable targets for the development of novel chemotherapeutics against human alveolar echinococcosis.