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

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.

Low dose radiation prevents doxorubicin-induced cardiotoxicity

“…Regarding the mechanisms by which LDR preserves mitochondrial integrity, we do not have direct evidence based on the present study; however we assumed the protective effects of LDR, as illustrated in Figure 8 , most likely due to its following reasons: (1) LDR stimulates Akt and Nrf2 functions via generating small amount of ROS [ 21 , 40 ] to up-regulate multiple antioxidants or free radical scavenging capacities [ 21 , 24 , 40 ]; (2) LDR-increased expression of mitochondrial superoxide dismutase [ 41 , 42 ] which may be mediated by LDR-up-regulated Nrf2 transcription function, contributing to the resistance of cardiac cells to DOX; (3) LDR-stimulated mitogen activated protein kinase that turn on cell survival signaling in normal tissues, but not in tumor tissue [ 40 , 43 ].…”

“… Based on previous published work from the authors own and others, we assume that LDR may generate small amount of ROS (a) that stimulates cardiac cells to express protective proteins [ 21 – 23 ]; (b) oxidizes Keap1 to disassociate Nrf2 that translocates to nucleus where Nrf2 transcriptionally up-regulates its down-stream antioxidant genes [ 21 , 40 – 42 ]; (c) stimulates ERK1/2 or ATM/Akt-mediated protective signaling pathways [ 21 , 43 ]; All these possible mechanisms protect mitochondrial damage from DOX, resulting in the protection from DOX-induced cardiac cell death and cardiac toxicity. …”

“…Several compounds, such as sulforaphane (SFN), are able to generate small amount of ROS to oxidize Keap1 to release Nrf2, thereby stabilizing Nrf2 function [ 46 , 47 ]. Therefore, we assume that LDR-generated small amounts of ROS may oxidize Keap1, thereby releasing and stabilizing Nrf2 that results in up-regulation of multiple antioxidants [ 21 , 40 ]. However, although both SFN and LDR can generate small amount of ROS to stimulate Nrf2 function, exposure to LDR is non-invasive while SFN must be administrated systemically so that LDR remains the best approach.…”

Intermittent low dose irradiation enhances the effectiveness of radio- and chemo-therapy for human colorectal adenocarcinoma cell line HT-29

“…ATM and p53 are two of the most important genes that are involed in cellular response to radiotherapy and chemotherapy. Yang et al found that the activation of ATM was the initiating event in LDR induced hormesis and adaptive response, and the distinct activation of ATM/AKT/GSK-3β signaling pathway may explain the differential biological effects between lung cancer cells and normal lung epithelial cells (18). Brazina et al showed that the interplay between ATM, p53 and DAxx plays a key role in the regulation of ionizing radiation or genotoxic drug-induced DNA damage (19).…”

Biological basis of radiation protection needs rejuvenation

“…When such research is done, results are often surprising, suggesting, e.g. hormesis at low doses of radiation (Sokolov and Neumann 2015) or different responses to radiation when cancer cells and their normal counterparts are compared (Yang et al 2016). Modeling and systems biology try at the very least to support the 'J shaped' cancer dose response and LNT at the same time (Lou et al 2012;Calabrese 2015).…”