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The loss of ATM (ataxia telangiectasia-mutated) gene function not only leads to AT disease, but also increases cytotoxicity by radiation and oxidative stress. This study aimed to explore the relationship between the intracellular ROS levels and ATM-mediated radiosensitivity and oxidative stress response in glioma cells. A gene knock-out system by siRNA technique was used in U87 cells, a glioma cell line, to suppress atm gene expression. The suppression of atm gene level was found to increase the intracellular ROS levels, retard cell proliferation rate, and increase the sensitivity of cellular lethality to oxidative stress. The increased ROS level in ATM-silenced U87 cells was reduced by the incubation of antioxidant N-acetylcysteine (NAC). The survival fraction following 2 or 4 Gy of radiation was also increased by NAC treatment. However, the losses of sub-lethal damage repair (SLDR) and potential lethal damage repair (PLDR) in ATM-silenced U87 cells were only partially recovered by NAC treatment. This indicates that there should be multiple pathways associated with ATM-mediated radiosensitivity and ROS level is one of them. While T98 cells, a glioma cell line with mutated p53, were tested, down-regulation of ATM on this cell line resulted in similar response to ionizing irradiation as that in U87 cells with functional p53, but further enhanced the response to oxidative stress. The addition effect of ATM and p53 on cell response to oxidative stress correlated with intracellular ROS levels. Our results suggest that p53 plays different roles on ATM-mediated radiosensitivity and response to oxidative stress in glioma cells.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA