Regulation of the radiosensitivity of tumor cells through HIF-1α dependent intracellular redox status after fractionated radiation  

作　　者：JIN Wensen KONG Zhaolu SHEN Zhifen JIN Yizun ZHANG Wukui 

机构地区：[1]Department of Nuclear Medicine, An-hui Medical University, Hefei, China [2]Eighth Laboratory, Institute of Radiation Medicine, Fudan University, Shanghai, China

出　　处：《Nuclear Science and Techniques》2010年第5期294-301,共8页核技术（英文）

基　　金：Supported by National Natural Science Foundation of China (Grant No. 30500143);Science Research Foundation of Anhui Medical University (Grant No. 010503101);College’ Science Research Program of Anhui Province (Grant No.KJ2010A189)

摘　　要：Tumor cells often develop resistance to radiotherapy by fractionated radiation possibly due to the heterogeneity and hypoxia in tumor tissue.However,the mechanism of refractory effect remains unclear.In the present study,a radioresistant variant HepG2/R60 cell line was isolated from human HepG2 cells by repeated exposure to radiation.The results showed that,after irradiation,the higher survival rate was in HepG2/R60 cells compared to parental cells.Hypoxia treatment could further increase the radioresistance of HepG2/R60 cells concomitant with high level of intracellular GSH and overexpression of HIF-1α.When hypoxic HepG2/R60 cells were pretreated with BSO,a GSH depleter,the refractory response was significantly reduced showing a decrease in intracellular GSH level,followed by the suppression of HIF-1α in hypoxic cells.Subsequent study found that the level of BCL-2 was down-regulated,targeted by HIF-1 prompting transcription in hypoxic cells.The effect of HIF-1α on the radiosensitivity of hypoxic cells was confirmed using YC-1,a specific inhibitor of HIF-1α.Consequently,our results suggest that the radiosensitivity of tumor cells might be regulated by fractionated radiation,and the radioresistance of cells induced by repeated exposure,under hypoxic condition,could be correlated with overexpression of HIF-1α dependent on the alteration of intracellular GSH contents.Tumor cells often develop resistance to radiotherapy by fractionated radiation possibly due to the heterogeneity and hypoxia in tumor tissue.However,the mechanism of refractory effect remains unclear.In the present study,a radioresistant variant HepG2/R60 cell line was isolated from human HepG2 cells by repeated exposure to radiation.The results showed that,after irradiation,the higher survival rate was in HepG2/R60 cells compared to parental cells.Hypoxia treatment could further increase the radioresistance of HepG2/R60 cells concomitant with high level of intracellular GSH and overexpression of HIF-1α.When hypoxic HepG2/R60 cells were pretreated with BSO,a GSH depleter,the refractory response was significantly reduced showing a decrease in intracellular GSH level,followed by the suppression of HIF-1α in hypoxic cells.Subsequent study found that the level of BCL-2 was down-regulated,targeted by HIF-1 prompting transcription in hypoxic cells.The effect of HIF-1α on the radiosensitivity of hypoxic cells was confirmed using YC-1,a specific inhibitor of HIF-1α.Consequently,our results suggest that the radiosensitivity of tumor cells might be regulated by fractionated radiation,and the radioresistance of cells induced by repeated exposure,under hypoxic condition,could be correlated with overexpression of HIF-1α dependent on the alteration of intracellular GSH contents.

关 键 词：放射敏感性 肿瘤细胞 细胞内 氧化还原 照射 缺氧诱导因子 GSH含量 组织缺氧 

分 类 号：Q279[生物学—细胞生物学] X591[环境科学与工程—环境工程]