雷帕霉素增强鼻咽癌放疗敏感性的分子机制研究  

Improvement of antitumor effect of ionizing radiation to treat nasopharyngeal carcinoma in combination with rapamycin

作　　者：邓立勇[1] 汪砥[1] 胡锦跃[1] 王桂华[1] 

机构地区：[1]长沙市中心医院肿瘤科,长沙410004

出　　处：《中国医师杂志》2016年第11期1642-1645,1649,共5页Journal of Chinese Physician

基　　金：湖南省卫生计生委项目（B2014-144）;长沙市科技局一般项目（k1406015-61）

摘　　要：目的探讨雷帕霉素对于鼻咽癌（NPC）放射治疗的增敏效果及其分子机制。方法体外实验以未经处理的细胞作为对照，用雷帕霉素、放射照射、雷帕霉素联合放射照射对鼻咽癌细胞进行处理，比较各组间S6和糖原合成酶激酶3S（GSK313）磷酸化、细胞周期蛋白CyclinD1的表达、肿瘤细胞克隆形成及残余γH2AX灶数量以及细胞周期进展。裸鼠体内接种鼻咽癌CNEl细胞，与体外实验同样分组处理，比较各组之间肿瘤的重量以及细胞周期蛋白CyclinD1和磷酸化s6的表达。结果雷帕霉素降低鼻咽癌细胞中的S6和GSK3~磷酸化以及CyclinD1表达；雷帕霉素处理后，鼻咽癌细胞存活率降低，DNA损伤率升高和G1期阻滞延长；体内研究结果显示雷帕霉素显著抑制肿瘤生长，并降低细胞周期蛋白D1和磷酸化S6表达水平。与单独治疗相比，雷帕霉素联合放射照射能进一步促进鼻咽癌细胞凋亡、DNA损伤率升高和G1期阻滞延长，进一步抑制肿瘤生长。结论雷帕霉素通过抑制Akt／哺乳动物雷帕霉素靶蛋白（mTOR）／S6和Akt／GSK313／细胞周期蛋白D1途径提高放射治疗鼻咽癌的效果。Objective To explore the possibility of rapamycin to up-regulate radiosensitivity of nasopharyngeal carcinoma （NPC） and its molecular mechanism. Methods In vitro, with untreated cells as the control, NPC cells were treated with rapamycin, irradiation （IR）, or both rapamycin and IR. Phosphorylation of S6 and GSK313, expression of Cyclin＇ D1, clonogenic survival, number of residual γH2AX foci, and cell cycle status between study groups were compared. In vivo, athymic mice bearing CNE1 tumor were similarly treated. Tumor weight, Cyclin D1 and phosphorylated S6 in the xenograft model were compared between study groups. Results The results showed that rapamycin alone decreased the phosphorylation of S6 and glycogen synthase kinase 313 （GSK313）, and the expression of Cyclin D1 in NPC cells. Thus, rapamy- cin-treated NPC cells had lower cell viability, higher DNA damage and more G1 arrest than the control, which was reflected by the in vivo study that rapamycin significantly attenuated tumor growth and decreased the levels of Cyclin D1 and phosphorylated S6. Moreover, the combination of rapamycin and IR caused the highest cell death, DNA damage, G1 arrest and tumor regression compared to those treated either alone. Conclusions Rapamycin up-regulate NPC radiosensitivity by inhibiting signal transduction of Akt/mammalian target of rapamycin （mTOR）/S6 pathway and Akt/GSK3[3 pathway, and by downregulating Cyclin D1 expression.

关 键 词：西罗莫司/药理学 鼻咽肿瘤/治疗 辐射耐受性/药物作用 放射疗法 蛋白质丝氨酸苏氨酸激酶/代谢 

分 类 号：R739.63[医药卫生—肿瘤]