European Journal of Cell Biology. 2015 Dec;94(12):653-60.
Role of AKT and ERK pathways in controlling sensitivity to ionizing radiation and adaptive response induced by low-dose radiation in human immune cells
Hyung Sun Parka, Ga Eun Youa, Kwang Hee Yanga, Ji Young Kima, Sungkwan Anb, Jie-Young Songc, Su-Jae Leed, Young-Khi Lime, Seon Young Nama, *
aLow-dose Radiation Research Team, Radiation Health Institute, Korea Hydro & Nuclear Power Co., LTD, Seoul 01450, Korea
bMolecular-Targeted Drug Research Center and Korea Institute for Skin and Clinical Sciences, Konkuk University, Seoul 05029, Korea
cDivision of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea
dDepartment of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Korea
eDepartment of Radiological Science, Gachon University, Incheon 21936, Korea
Despite many studies of the effect of ionizing radiation, biological mechanisms of action might differ greatly depend on dose, dose rate, and cell type. This study was performed to explore the effects of low- and high-dose radiation in human immune cell lines. We examined cell sensitivity after irradiation with 0.05, 0.1, or 2 Gy in two normal cell lines and three tumor cell lines. Low-dose radiation of 0.05 and 0.1 Gy had no effect on cell survival in any tested cell line, with the exception of IM-9 cells, whose viability was transiently increased. However, IM-9 and C1R-sB7 cells were very sensitive to high-dose radiation-induced cell death, whereas Jurkat and JM1 cells showed moderate sensitivity, and THP-1 cells were completely resistant. This radiosensitivity was correlated with basal AKT activation, which is induced by phosphorylation. In radiosensitive IM-9 cells, priming with chronic low-dose irradiation blocked cell death induced by high-dose radiation challenge via inhibition of caspase activation and PARP cleavage. AKT phosphorylation was not altered in IM-9 cells, but ERK phosphorylation was greatly elevated immediately after chronic low-dose irradiation. Taken together, our results suggest that the different responses of normal and tumor cells to low-dose and high-dose radiation depend on AKT activation, which is regulated by protein phosphatase 2 (PP2A). In radiosensitive normal cells lacking basal AKT activity, chronic low-dose radiation increases activation of the ERK pathway, which plays an important role in the adaptive response to radiation, providing a very important insight into understanding the effects of ionizing radiation on health.
KEYWORDS: AKT; Apoptosis; ERK; Ionizing radiation; Low-dose
The biological effects of low-dose radiation could not have been entirely predicted and are considerably more complex than those of high-dose studies (1). Those events may result from signal transduction pathways that are different from those seen with high-dose and high-dose-rate radiation.
Low-dose radiation was previously shown to enhance cell protection through activation of the AKT (protein kinase B, PKB)/nuclear factor-kappa B (NF-κB) pathway (2). The mitogen-activated protein kinase (MAPK) superfamily is another important signaling pathway induced by ionizing radiation (3). Thus we hypothesized that the activations of AKT or MAPKs pathway might be associated with cellular protective responses induced by low-dose radiation.
We demonstrated that ionizing radiation affects cell survival in a cell-type-dependent manner and that prior exposure of cells to low-dose radiation induces an adaptive response to high-dose radiation via blockade of high-dose-induced apoptosis in human immune cells. Whereas many factors may affect the cellular response to radiation exposure, we demonstrated that AKT activity is a critical mechanism in determination of radioresistance in tumor cells. However, in normal cells lacking basal AKT activity, low-dose radiation complementarily activated the ERK pathway, showing that is very important for the adaptive response to high-dose ionizing radiation (Figure 1).
Figure 1. Scheme of cellular mechanism for radio-resistance and adaptive response in human immune cells
The importance of this study: This study suggests that the differential sensitivity of non-tumor and tumor cells to low-dose and high-dose radiation depends on AKT activity which is regulated by PP2A, a potent inhibitor of activation of the AKT pathway. Interestingly, activation of the ERK pathway is complementarily induced by low-dose radiation in normal immune cells lacking basal AKT activity. Precisely, chronic low-dose radiation might inhibit cell death induced by cytotoxic high-dose radiation through modulation of the activation level of the ERK pathway. These results will be helpful in understanding the regulatory mechanism underlying the cellular response to chronic low-dose radiation and provide important insights for the design of future studies to better understand the cell-type- and molecular-condition-dependent biological responses to ionizing radiation.
- Amundson SA, Lee RA, Koch-Paiz CA, Bittner ML, Meltzer P, Trent JM, Fornace AJ Jr., 2003. Differential responses of stress genes to low dose-rate irradiation. Mol. Cancer Res. 1:445-452.
- Park HS, Seong KM, Kim JY, Kim CS, Yang KH, Jin YW, Nam SY, 2013. Chronic low-dose radiation inhibits the cells death by cytotoxic high-dose radiation increasing the level of AKT and acinus proteins via NF-κB activation. Int. J. Radiat. Biol. 89:371-377.
- Liang X, So YH, Cui J, Ma K, Xu X, Zhao Y, Cai L, Li W. 2011. The low-dose ionizing radiation stimulates cell proliferation via activation of the MAPK/ERK pathway in rat cultured mesenchymal stem cells. J Radiat Res 52(3):380-386.
Acknowledgements: This work was supported by Grant No. 20131610101840 from the Ministry of Trade, Industry & Energy (MOTIE), Republic of Korea.
Seon Young Nam, Ph.D.
Low-dose Radiation Research Team
Radiation Health Institute
Korea Hydro & Nuclear Power Co. Ltd.
Seoul 01450, Korea