Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer
Authors: Peter C Keng
Xiaodong Yang
Mingjing Shen
Fuquan Zhang
Ying Tsai
Yuhchyau Chen
Yongbing Chen
Li Yang
Soo Ok Lee
Journal: Cancer biology & therapy (2017)
Discipline: CLINICAL MEDICINE
Keywords: ATM; Mcl-1; cisplatin-resistance; cisplatin-sensitivity; non-small cell lung cancer.
Affiliations: 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.

Abstract:  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. 

Retracted: No

PubPeer comments:
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 Figure 4A. * Green boxes: Two panels representing different treatments appear to show an overlap. Could the authors please check? ![file] , 
 This article now has two corrections. Correction 1, 24 February 2020: https: www.tandfonline.com doi full 10.1080 15384047.2020.1733804  In the version of Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer by Fuquan Zhang, Mingjing Shen, Li Yang, Xiaodong Yang, Ying Tsai, Peter C. Keng, Yongbing Chen, Soo Ok Lee, and Yuhchyau Chen published online September 13, 2017 and in print in its official publication Issue 8, Volume 18, the GADPH blot line on Figure 3A was inappropriately duplicated from a different experiment and mistakenly incorporated into Figure 3A of this manuscript. The correct image of the blot line has been provided below. These results are consistent with the original findings reported in the manuscript. The authors apologize for any inconvenience caused by this error. Correction 2: 12 July 2021: https: www.tandfonline.com doi full 10.1080 15384047.2021.1937449  n the version of Simultaneous targeting of ATM and Mcl-1 increases cisplatin sensitivity of cisplatin-resistant non-small cell lung cancer by Fuquan Zhang, Mingjing Shen, Li Yang, Xiaodong Yang, Ying Tsai, Peter C. Keng, Yongbing Chen, Soo Ok Lee, and Yuhchyau Chen published online September 13, 2017 and in print in its official publication Issue 8, Volume 18, the Mcl1 A549CisR-siATM shMcl1 image in Figure 4A is incorrect and the Authors and Editors wish to correct the literature. The correct image is displayed below. The Authors recognise that the publication of a second correction notice is unusual and apologize for the inconvenience caused. Upon an internal investigation from the institution, it was determined that the authors had incorrectly labelled their data files, leading to the publication of incorrect images. The Authors have reviewed all other images within the article and confirm that they are accurate and reflect the experiments performed. The Editor is satisfied that the results and conclusions remain consistent with the original findings reported in the article. ,