Cdc6 contributes to cisplatin-resistance by activation of ATR-Chk1 pathway in bladder cancer cells

// Sansan Chen 1, 2, * , Xinglu Chen 2, * , Gui’e Xie 3, * , Yue He 2 , Daoyu Yan 2 , Dianpeng Zheng 2 , Shi Li 1 , Xinyang Fu 1 , Yeping Li 1 , Xiang Pang 1 , Zhiming Hu 2 , Hongwei Li 2 , Wanlong Tan 1 , Jinlong Li 2 1 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China 2 Institute of Biotherapy, School of Biotechnology, Southern Medical University, Guangzhou, Guangdong, China 3 KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China * These authors contributed equally to this work Correspondence to: Jinlong Li, email: lijinlong@smu.edu.cn Wanlong Tan, email: tanwanlong@gmail.com Hongwei Li, email: hongwei1@yahoo.com Keywords: Cdc6, ATR, cisplatin-resistance, bladder cancer Received: January 07, 2016     Accepted: May 08, 2016     Published: May 26, 2016 ABSTRACT 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.