机构：[a]Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA[b]Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China
Development of cisplatin-resistance is an obstacle in non-small cell lung cancer (NSCLC) therapeutics. To investigate which molecules are associated with cisplatin-resistance, we analyzed expression profiles of several DNA repair and anti-apoptosis associated molecules in parental (A549P and H157P) and cisplatin-resistant (A549CisR and H157CisR) NSCLC cells. We detected constitutively upregulated nuclear ATM and cytosolic Mcl-1 molcules in cisplatin-resistant cells compared with parental cells. Increased levels of phosphorylated ATM (p-ATM) and its downstream molecules, CHK2, p-CHK2, p-53, and p-p53 were also detected in cisplatin-resistant cells, suggesting an activation of ATM signaling in these cells. Upon inhibition of ATM and Mcl-1 expression/activity using specific inhibitors of ATM and/or Mcl-1, we found significantly enhanced cisplatin-cytotoxicity and increased apoptosis of A549CisR cells after cisplatin treatment. Several A549CisR-derived cell lines, including ATM knocked down (A549CisR-siATM), Mcl-1 knocked down (A549CisR-shMcl1), ATM/Mcl-1 double knocked down (A549CisR-siATM/shMcl1) as well as scramble control (A549CisR-sc), were then developed. Higher cisplatin-cytotoxicity and increased apoptosis were observed in A549CisR-siATM, A549CisR-shMcl1, and A549CisR-siATM/shMcl1 cells compared with A549CisR-sc cells, and the most significant effect was shown in A549CisR-siATM/shMcl1 cells. In in vivo mice studies using subcutaneous xenograft mouse models developed with A549CisR-sc and A549CisR-siATM/shMcl1 cells, significant tumor regression in A549CisR-siATM/shMcl1 cells-derived xenografts was observed after cisplatin injection, but not in A549CisR-sc cells-derived xenografts. Finally, inhibitor studies revealed activation of Erk signaling pathway was most important in upregulation of ATM and Mcl-1 molcules in cisplatin-resistant cells. These studies suggest that simultaneous blocking of ATM/Mcl-1 molcules or downstream Erk signaling may recover the cisplatin-resistance of lung cancer.
第一作者机构：[a]Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA[b]Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China
共同第一作者：
通讯作者：
通讯机构：[*1]Department of Radiation Oncology, James P. Wilmot Cancer Center, University of Rochester, 601 Elmwood Ave., Box 647, Rochester, NY 14642, USA.
推荐引用方式(GB/T 7714)：
Fuquan Zhang,Mingjing Shen,Li Yang,et al.Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer[J].CANCER BIOLOGY & THERAPY.2017,18(8):606-615.doi:10.1080/15384047.2017.1345391.
APA：
Fuquan Zhang,Mingjing Shen,Li Yang,Xiaodong Yang,Ying Tsai...&Yuhchyau Chen.(2017).Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer.CANCER BIOLOGY & THERAPY,18,(8)
MLA：
Fuquan Zhang,et al."Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer".CANCER BIOLOGY & THERAPY 18..8(2017):606-615
