State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
Parasitology Research Laboratory, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
PLoS Negl Trop Dis. 2019 May 16;13(5):e0007425. doi: 10.1371/journal.pntd.0007425. eCollection 2019 May.
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.
绦虫多房棘球蚴幼虫的肿瘤样生长导致人类泡型包虫病，这是一种主要影响肝脏的严重疾病。生殖细胞是成虫干细胞的一个群体，对于寄生虫在宿主中的幼虫生长和发育至关重要。生殖细胞池的维持依赖于它们广泛增殖和自我更新的能力，这需要对细胞分裂周期进行精确控制。靶向细胞分裂进展的调节剂可能会损害生殖细胞群体，从而阻碍寄生虫的生长。
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 Aurora 激酶的成员具有显著的相似性，Aurora 激酶是必不可少的有丝分裂激酶，在细胞分裂中发挥关键作用。我们的数据表明，EmAURKA 和 EmAURKB 在多房棘球绦虫的生殖细胞中积极表达。用低浓度的 MLN8237（Aurora A 和 B 的双重抑制剂）处理会导致生殖细胞在有丝分裂过程中出现染色体缺陷，而较高浓度的 MLN8237 会导致生殖细胞的胞质分裂失败，导致多核细胞。Aurora 激酶活性的抑制最终导致多房棘球绦虫生殖细胞群体的耗竭，从而抑制寄生虫的幼虫生长。
结论/意义：我们的数据表明 Aurora 激酶在多房棘球绦虫有丝分裂进程的调节和生殖细胞的维持中起着至关重要的作用，并表明 Aurora 激酶是开发针对人类泡型包虫病的新型化学治疗药物的有前途的可药用靶标。
