Exp Mol Med.  2005 Aug;37(4):282-289.

Ionizing radiation induces blockade of c-Jun N-terminal kinasedependent cell death pathway in amanner correlated with p21Cip/WAF1 induction in primary cultured normal human fibroblasts

Affiliations
  • 1Laboratory of Radiation Tumor Physiology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea. hdum@kcch.re.kr
  • 2Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
  • 3Laboratory of Radiation Experimental Therapeutics, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.

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 H2O2. This type of cell death was accompanied by JNK activation, and was reversed by the use of a JNK-specific inhibitor SP600125. Interestingly, H2O2 failed to kill the fibroblasts when these cells were pre-irradiated, 24 h before H2O2 treatment, with 0.25-0.5 Gy of gamma-rays. These cytoprotective doses of gamma-rays did not enhance cellular capacity to degrade H2O2, but elevated cellular levels of p21Cip/WAF1, a p53 target that can suppress H2O2-induced cell death by blocking JNK activation. Consistently, H2O2-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.

Keyword

cell death; fibroblasts; hydrogen peroxide; radiation, ionizing; JNK mitogen-activated protein kinases

MeSH Terms

Antioxidants/pharmacology
Cell Death
Cells, Cultured
Enzyme Activation/radiation effects
Fibroblasts/enzymology/radiation effects
*Gamma Rays
Heat-Shock Proteins/metabolism
Humans
JNK Mitogen-Activated Protein Kinases/*antagonists & inhibitors
Oxidative Stress/*radiation effects
Research Support, Non-U.S. Gov't
Water/pharmacology
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