Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6
Norcantharidin inhibits DNA replication and induces mitotic catastrophe by degrading initiation protein Cdc6
复制标题
去甲斑蝥素通过降解起始蛋白 Cdc6 抑制 DNA 复制并诱导有丝分裂灾难
DOI：
10.3892/ijmm.2013.1359
复制
发表时间：
2013-07-01
影响因子：
5.4
通讯作者：
Li, Jinlong
中科院分区：
文献类型：
--
作者：
Chen, Sansan;Wan, Pei;Li, Jinlong
Cdc6是DNA复制必需的起始蛋白，也参与ATR检查点通路，在肿瘤发生中起重要作用。它参与雄激素受体（AR）信号转导，促进前列腺癌（PCa）的恶性进展。在这项研究中，我们报道了去甲斑蝥素（NCTD）诱导DU145 PCa细胞中Cdc6的降解，从而干扰预复制复合物（pre-RCs）的组装，抑制DNA复制。此外，NCTD治疗阻断了ATR与染色质的结合，在羟基脲（HU）诱导的应激下，细胞进入有丝分裂，表明ATR检查点被规避。NCTD治疗后也观察到异常的有丝分裂和细胞凋亡。最后，NCTD与另一种有丝分裂抑制剂紫杉醇联合具有较强的协同细胞毒作用，联合指数（CI）
Cdc6, an essential initiation protein for DNA replication, also participates in the ATR checkpoint pathway and plays a vital role in tumorigenesis. It is involved in the androgen receptor (AR) signal transduction and promotes the malignant progression of prostate cancer (PCa). In this study, we report that norcantharidin (NCTD) induces the degradation of Cdc6 in DU145 PCa cells and as a result, the assembly of pre-replication complexes (pre-RCs) was disturbed and DNA replication was inhibited. Furthermore, treatment with NCTD blocked ATR binding to chromatin and the cells progressed into mitosis under stress induced by hydroxyurea (HU), indicating that the ATR checkpoint was evaded. Aberrant mitosis and hence, apoptosis were also observed following treatment with NCTD. Finally, NCTD exerted strong synergistic cytotoxic effects in combination with another mitotic inhibitor, paclitaxel, [combination index (CI