Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma
Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma
复制标题
DOI：
10.1158/0008-5472.can-08-1693
复制
发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Santoro, Massimo
中科院分区：
文献类型：
--
作者：
Nappi, Tito Claudio;Salerno, Paolo;Santoro, Massimo
间变性甲状腺癌（ATC）是最具侵袭性和化疗耐药的癌症之一。丝氨酸/苏氨酸激酶polo样激酶1 （PLK1）是有丝分裂过程中多个步骤的关键调节因子，在ATC中高度表达。在这里，我们将BI 2536 PLK1抑制剂用于ATC和未转化的甲状腺滤泡细胞。我们的数据显示，ATC细胞依赖于高水平的PLK1活性，以促进增殖、存活、非锚定生长和致瘤性。在纳摩尔剂量的BI 2536治疗下，ATC细胞在S期正常进展，但此后直接因有丝分裂停止而死亡。免疫荧光显微镜、免疫印迹和流式细胞术分析显示，PLK1阻断后，ATC细胞停留在早期中期，DNA含量为4N。处理后的ATC细胞积累了磷酸组蛋白H3，并表现出特征性的有丝分裂（Polo）纺锤体畸变。与ATC细胞相比，未转化的甲状腺细胞对BI 2536诱导的细胞周期效应的易感性低3.2- 18.4倍。这些发现确定PLK1是ATC分子治疗的一个有希望的靶点。[癌症研究2009；69 (5): 1916 - 23)
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and chemoresistant cancers. The serine/threonine kinase Polo-like kinase 1 (PLK1), a key regulator of multiple steps during mitotic progression, is highly expressed in ATC. Here, we used the BI 2536 PLK1 inhibitor on ATC and nontransformed thyroid follicular cell tines. Our data show that ATC cells are addicted to high levels of PLK1 activity for proliferation, survival, anchorage-independent growth, and tumorigenicity. On treatment with nanomolar doses of BI 2536, ATC cells progressed normally through S phase but died thereafter, directly from mitotic arrest. Immunofluorescence microscopy, immunoblot, and flow cytometry analysis showed that, on PLK1 blockade, ATC cells arrested in prometaphase with a 4N DNA content. Treated ATC cells accumulated phosphohistone H3 and displayed characteristic mitotic (Polo) spindle aberrations. Nontransformed thyroid cells were 3.2- to 18.4-fold less susceptible to BI 2536-induced cell cycle effects compared with ATC cells. These findings identify PLK1 as a promising target for the molecular therapy of ATC. [Cancer Res 2009;69(5):1916-23]