Gao Zhen, Sarsour Ehab H, Kalen Amanda L, Li Ling, Kumar Maneesh G, Goswami Prabhat C
Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USA.
Free Radic Biol Med. 2008 Dec 1;45(11):1501-9. doi: 10.1016/j.freeradbiomed.2008.08.009. Epub 2008 Aug 14.
This study investigates the hypothesis that CuZn superoxide dismutase (SOD1) overexpression confers radioresistance to human glioma cells by regulating the late accumulation of reactive oxygen species (ROS) and the G(2)/M-checkpoint pathway. U118-9 human glioma cells (wild type, neo vector control, and stably overexpressing SOD1) were irradiated (0-10 Gy) and assayed for cell survival, cellular ROS levels, cell-cycle-phase distributions, and cyclin B1 expression. SOD1-overexpressing cells were radioresistant compared to wild-type (wt) and neo vector control (neo) cells. Irradiated wt and neo cells showed a significant increase (approximately twofold) in DHE fluorescence beginning at 2 days postirradiation, which remained elevated at 8 days postirradiation. Interestingly, the late accumulation of ROS was suppressed in irradiated SOD1-overexpressing cells. The increase in ROS levels was followed by a decrease in cell growth and viability and an increase in the percentage of cells with sub-G(1) DNA content. SOD1 overexpression enhanced radiation-induced G(2) accumulation within 24 h postirradiation, which was accompanied by a decrease in cyclin B1 mRNA and protein levels. These results support the hypothesis that long after radiation exposure a "metabolic redox response" regulates radiosensitivity of human glioma cells.
铜锌超氧化物歧化酶（SOD1）的过表达通过调节活性氧（ROS）的晚期积累和G(2)/M检查点途径赋予人胶质瘤细胞放射抗性。对U118-9人胶质瘤细胞（野生型、新载体对照和稳定过表达SOD1的细胞）进行照射（0 - 10 Gy），并检测细胞存活率、细胞内ROS水平、细胞周期阶段分布和细胞周期蛋白B1表达。与野生型（wt）和新载体对照（neo）细胞相比，过表达SOD1的细胞具有放射抗性。照射后的wt和neo细胞在照射后2天开始DHE荧光显著增加（约两倍），并在照射后8天仍保持升高。有趣的是，照射后的过表达SOD1的细胞中ROS的晚期积累受到抑制。ROS水平升高后，细胞生长和活力下降，亚G(1) DNA含量的细胞百分比增加。SOD1过表达增强了照射后24小时内辐射诱导的G(2)期积累，同时细胞周期蛋白B1的mRNA和蛋白水平下降。这些结果支持了以下假说：在辐射暴露后很长时间，“代谢氧化还原反应”调节人胶质瘤细胞的放射敏感性。
