Cdc6 contributes to cisplatin-resistance by activation of ATR-Chk1 pathway in bladder cancer cells.
Cdc6 contributes to cisplatin-resistance by activation of ATR-Chk1 pathway in bladder cancer cells.
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Cdc6 通过激活膀胱癌细胞中的 ATR-Chk1 通路导致顺铂耐药
DOI：
10.18632/oncotarget.9616
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发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Chen S;Chen X;Xie G;He Y;Yan D;Zheng D;Li S;Fu X;Li Y;Pang X;Hu Z;Li H;Tan W;Li J
DNA损伤反应的高活化与顺铂（CDDP）耐药有关，这是膀胱癌治疗的严重障碍。cdc 6在肿瘤的恶性进展中起重要作用。在这里，我们报道了Cdc 6表达在膀胱癌组织中上调，并且与高肿瘤分级呈正相关。Cdc 6缺失可减弱膀胱癌细胞的恶性特性，包括DNA复制、迁移和侵袭。此外，更高水平的染色质结合Cdc 6和ATR检测CDDP耐药膀胱癌细胞比亲本膀胱癌细胞。有趣的是，Cdc 6的下调可以增强膀胱癌细胞和CDDP耐药膀胱癌细胞对CDDP的敏感性。Cdc 6缺失消除了CDDP引起的S期阻滞，通过失活ATR-Chk 1-Cdc 25 C途径导致异常有丝分裂。我们的研究结果表明，Cdc 6可能是一个有前途的目标，克服CDDP耐药膀胱癌。
High activation of DNA damage response is implicated in cisplatin (CDDP) resistance which presents as a serious obstacle for bladder cancer treatment. Cdc6 plays an important role in the malignant progression of tumor. Here, we reported that Cdc6 expression is up-regulated in bladder cancer tissues and is positively correlated to high tumor grade. Cdc6 depletion can attenuate the malignant properties of bladder cancer cells, including DNA replication, migration and invasion. Furthermore, higher levels of chromatin-binding Cdc6 and ATR were detected in CDDP-resistant bladder cancer cells than in the parent bladder cancer cells. Intriguingly, down-regulation of Cdc6 can enhance sensitivity to CDDP both in bladder cancer cells and CDDP-resistant bladder cancer cells. Cdc6 depletion abrogates S phase arrest caused by CDDP, leading to aberrant mitosis by inactivating ATR-Chk1-Cdc25C pathway. Our results indicate that Cdc6 may be a promising target for overcoming CDDP resistance in bladder cancer.
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