During radiotherapy of cancer, neighboring normal cells may receive sub-lethal doses of radiation. To investigate whether such low levels of radiation modulate normal cell responses to death stimuli, primary cultured human fibroblasts were exposed to various doses of γ-rays. Analysis of cell viability using an exclusion dye propidium iodide revealed that the irradiation up to 10 Gy killed the fibroblasts only to a minimal extent. In contrast, the cells efficiently lost their viability when exposed to 0.5-0.65 mM H2O2. This type of cell death was accompanied by JNK activation, and was reversed by the use of a JNK-specific inhibitor SP600125. Interestingly, H 2 O 2 failed to kill the fibroblasts when these cells were pre-irradiated, 24 h before H 2 O 2 treatment, with 0.25-0.5 Gy of γ-rays. These cytoprotective doses of γ-rays did not enhance cellular capacity to degrade H2O2, but elevated cellular levels of p21 Cip/WAF1 , a p53 target that can suppress H 2 O 2 -induced cell death by blocking JNK activation. Consistently, H 2 O 2 -induced JNK activation was dramatically suppressed in the pre-irradiated cells. The overall data suggests that ionizing radiation can impart normal fibroblasts with a survival advantage against oxidative stress by blocking the process leading to JNK activation.
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