Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers
Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers
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DOI：
10.1073/pnas.1719760115
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发表时间：
2018-02-20
影响因子：
11.1
通讯作者：
Dmitrovsky, Ethan
中科院分区：
文献类型：
--
作者：
Kawakami, Masanori;Mustachio, Lisa Maria;Dmitrovsky, Ethan
Polo-like kinase 4（PLK 4）是一种丝氨酸/苏氨酸激酶，调节中心粒的复制。CFI-400945是一种高度选择性的PLK 4抑制剂，可解除中心粒复制的调节，导致非整倍体癌症的有丝分裂缺陷和死亡。先前的工作通过显示CFI-400945引起鼠和人肺癌细胞的多倍性、生长抑制和凋亡性死亡而得到实质性扩展，尽管表达突变的KRAS或p53。通过碘化丙啶（PI）染色的DNA含量分析显示具有> 4 N DNA含量（多倍性）的细胞在CFI-400945处理后显著增加。对中心体数目和有丝分裂纺锤体进行评分。CFI-400945处理在肺癌细胞中产生额外的中心体和有丝分裂缺陷。在具有同系肺癌异种移植物的小鼠中确定了CFI-400945的体内抗肿瘤活性。在耐受良好的剂量下，肺肿瘤生长受到显著抑制。在CFI-400945治疗后切除的肺癌的磷组蛋白H3染色证实了异常有丝分裂的存在。使用癌症基因组图谱（TCGA）和含有正常和恶性肺组织的微阵列的RNA原位杂交（RNA ISH）探索人肺癌中PLK 4表达谱。PLK 4在肺癌组织中的表达显著高于正常肺组织（P < 0.05），并对肺癌患者的生存率产生不利影响。有趣的是，细胞周期蛋白依赖性激酶2（CDK 2）拮抗作用与PLK 4抑制作用协同作用。总之，PLK 4抑制单独或作为组合方案的一部分是对抗肺癌的有希望的方法。
Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication. CFI-400945 is a highly selective PLK4 inhibitor that deregulates centriole duplication, causing mitotic defects and death of aneuploid cancers. Prior work was substantially extended by showing CFI-400945 causes polyploidy, growth inhibition, and apoptotic death of murine and human lung cancer cells, despite expression of mutated KRAS or p53. Analysis of DNA content by propidium iodide (PI) staining revealed cells with >4N DNA content (polyploidy) markedly increased after CFI-400945 treatment. Centrosome numbers and mitotic spindles were scored. CFI-400945 treatment produced supernumerary centrosomes and mitotic defects in lung cancer cells. In vivo antineoplastic activity of CFI-400945 was established in mice with syngeneic lung cancer xenografts. Lung tumor growth was significantly inhibited at well-tolerated dosages. Phosphohistone H3 staining of resected lung cancers following CFI-400945 treatment confirmed the presence of aberrant mitosis. PLK4 expression profiles in human lung cancers were explored using The Cancer Genome Atlas (TCGA) and RNA in situ hybridization (RNA ISH) of microarrays containing normal and malignant lung tissues. PLK4 expression was significantly higher in the malignant versus normal lung and conferred an unfavorable survival (P < 0.05). Intriguingly, cyclin dependent kinase 2 (CDK2) antagonism cooperated with PLK4 inhibition. Taken together, PLK4 inhibition alone or as part of a combination regimen is a promising way to combat lung cancer.