Cell Division and Cancer Group, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, E-28029, Madrid, Spain.
Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Nat Commun. 2018 Aug 1;9(1):3012. doi: 10.1038/s41467-018-05429-5.
Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression results in abnormal chromosome segregation and cytokinesis, generating polyploid cells with reduced proliferative potential. Mechanistically, these cytokinesis defects correlate with defective loading of Cep55 and ESCRT complexes to the abscission bridge, in a Plk1 kinase-dependent manner. In vivo, Plk1 overexpression prevents the development of Kras-induced and Her2-induced mammary gland tumors, in the presence of increased rates of chromosome instability. In patients, Plk1 overexpression correlates with improved survival in specific breast cancer subtypes. Therefore, despite the therapeutic benefits of inhibiting Plk1 due to its essential role in tumor cell cycles, Plk1 overexpression has tumor-suppressive properties by perturbing mitotic progression and cytokinesis.
丝氨酸苏氨酸激酶 1（Plk1）在广泛的人类肿瘤中过度表达，常被认为是一种癌基因和有吸引力的癌症靶点。然而，它对肿瘤发展的贡献尚不清楚。在这里，我们使用一种新的诱导型敲入小鼠模型报告称，Plk1 的过表达导致异常的染色体分离和胞质分裂，产生增殖潜力降低的多倍体细胞。从机制上讲，这些胞质分裂缺陷与 Cep55 和 ESCRT 复合物以 Plk1 激酶依赖性方式向胞质分裂桥的加载缺陷相关。在体内，Plk1 的过表达可防止 Kras 诱导和 Her2 诱导的乳腺肿瘤的发展，同时伴有染色体不稳定性的增加。在患者中，Plk1 的过表达与特定乳腺癌亚型的生存改善相关。因此，尽管由于 Plk1 在肿瘤细胞周期中的重要作用而抑制 Plk1 具有治疗益处，但 Plk1 的过表达通过扰乱有丝分裂进程和胞质分裂而具有肿瘤抑制特性。
