title: 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.
abstract: 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.
authors.affiliation: Laboratory of Radiation Tumor Physiology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Cho
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Lee
authors.forename: In Hwa
authors.initials: IH
authors.lastname: Bae
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.forename: Su-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
mesh_terms: 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
chemical_list: D000975:Antioxidants; D006360:Heat-Shock Proteins; D014867:Water; D048031:JNK Mitogen-Activated Protein Kinases