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

Guozi Yang,Jifan Hu,Chao Niu,Lei Zhou,Xiao Chen,Dehai Yu,Lihua Dong,Fujun Han,Jiuwei Cui,Lu Cai,Yuguang Zhao,Wei Li,Xue Wen,Huimin Tian,Xiaoying Zhang,Xinyue Liang

doi:10.18632/oncotarget.12379

Guozi Yang, Jifan Hu + Show 14 more

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https://doi.org/10.18632/oncotarget.12379

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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.

Highlights

Conventional radiation therapy with daily doses of 1–2 Gy is a well-established and effective form of cancer treatment
ataxia telangiectasia mutated (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
In the same dose range of Low-dose radiation (LDR), most studies have confirmed that the hormesis and adaptive response were absent in cancer cells [26, 27]

Summary

Introduction

Conventional radiation therapy with daily doses of 1–2 Gy is a well-established and effective form of cancer treatment. Accumulating evidence suggests that low-dose radiation (LDR) usually defined as ≤ 0.2 Gy at low linear energy transfer (LET) or ≤ 0.05 Gy at high LET can induce hormesis [2], which is linked to cell growth, increased longevity and embryo production, and enhanced immune response to disease [3, 4]. LDR induces adaptive response, which protects cell and tissue against injury caused by a subsequent high-dose radiation (HDR) [5]. Some of the stimulatory effects may result in adaptive response to subsequent HDR, while hormesis is the first response after exposure to adaptive response doses of radiation

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