Distinct biological effects of low-dose radiation on normal and cancerous human lung cells are mediated by ATM signaling

Abstract

// Guozi Yang 1, 2, * , Dehai Yu 1, * , Wei Li 1 , Yuguang Zhao 1 , Xue Wen 1 , Xinyue Liang 1 , Xiaoying Zhang 1 , Lei Zhou 1 , Jifan Hu 1 , Chao Niu 1 , Huimin Tian 1 , Fujun Han 1 , Xiao Chen 1 , Lihua Dong 2 , Lu Cai 1, 3 , Jiuwei Cui 1 1 Cancer Center, The First Hospital of Jilin University, Changchun 130021, China 2 Department of Radiation-Oncology, The First Hospital of Jilin University, Changchun 130021, China 3 Kosair Children’s Hospital Research Institute, Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292, USA * These authors contributed equally to this work Correspondence to: Jiuwei Cui, email: cuijw@jlu.edu.cn Lu Cai, email: L0cai001@louisville.edu Keywords: low-dose radiation, normal lung cells, lung cancer cells, biological effects, ATM Received: February 03, 2016      Accepted: September 25, 2016      Published: September 30, 2016 ABSTRACT Low-dose radiation (LDR) induces hormesis and adaptive response in normal cells but not in cancer cells, suggesting its potential protection of normal tissue against damage induced by conventional radiotherapy. However, the underlying mechanisms are not well established. We addressed this in the present study by examining the role of the ataxia telangiectasia mutated (ATM) signaling pathway in response to LDR using A549 human lung adenocarcinoma cells and HBE135-E6E7 (HBE) normal lung epithelial cells. We found that LDR-activated ATM was the initiating event in hormesis and adaptive response to LDR in HBE cells. ATM activation increased the expression of CDK4/CDK6/cyclin D1 by activating the AKT/glycogen synthase kinase (GSK)-3β signaling pathway, which stimulated HBE cell proliferation. Activation of ATM/AKT/GSK-3β signaling also increased nuclear accumulation of nuclear factor erythroid 2-related factor 2, leading to increased expression of antioxidants, which mitigated cellular damage from excessive reactive oxygen species production induced by high-dose radiation. However, these effects were not observed in A549 cells. Thus, the failure to activate these pathways in A549 cells likely explains the difference between normal and cancer cells in terms of hormesis and adaptive response to LDR.