Ionizing radiation induces blockade of c-Jun N-terminal kinase-dependent cell death pathway in a manner correlated with p21(Cip/WAF1) induction in primary cultured normal human fibroblasts.
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 gamma-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 H(2)O(2). 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 gamma-rays. These cytoprotective doses of gamma-rays did not enhance cellular capacity to degrade H(2)O(2), 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.
Cho
Eun Sook
ES
Laboratory of Radiation Tumor Physiology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
Lee
Seung Bum
SB
Bae
In Hwa
IH
Lee
Yun-Sil
YS
Lee
Su-Jae
SJ
Um
Hong-Duck
HD
D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000528:radiation effects; D005347:Fibroblasts / Q000201:enzymology / Q000528:radiation effects; D005720:Gamma Rays; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000528:radiation effects*; D014867:Water / Q000494:pharmacology
D000975:Antioxidants; D006360:Heat-Shock Proteins; D014867:Water; D048031:JNK Mitogen-Activated Protein Kinases