Src酪氨酸激酶抑制剂dasatinib对人食管鳞癌细胞KYSE180生长及凋亡的影响  

Effects of Src tyrosine kinase inhibitor dasatinib on the proliferation and apoptosis of human esophageal squamous cell carcinoma cell line KYSE180

作　　者：王莉[1] 王如文[1] 蒋耀光[1] 赵云平[1] 龚太乾[1] 郭伟[1] 

机构地区：[1]第三军医大学大坪医院野战外科研究所,全军胸外科中心,重庆400042

出　　处：《肿瘤》2012年第7期483-488,共6页Tumor

基　　金：国家自然科学基金资助项目(编号:81101891);中国博士后科学基金资助项目(编号:20100481469)

摘　　要：目的:探讨Src酪氨酸激酶抑制剂dasatinib对人食管鳞癌细胞生长和凋亡的影响及其相关机制。方法:采用蛋白质印迹法检测食管鳞癌细胞株KYSE180、EC109、KYSE30和人永生化食管上皮细胞株SHEE中总Src和磷酸化Src激酶的表达。用不同剂量的Src酪氨酸激酶抑制剂dasatinib作用KYSE180细胞后,分别采用MTT法、FCM法、蛋白质印迹法和裸鼠皮下移植瘤实验观察dasatinib对KYSE180细胞Src激酶的抑制作用,以及对细胞增殖、细胞周期、细胞凋亡和裸鼠皮下移植瘤的影响。结果:KYSE180、EC109和KYSE30细胞中Src激酶显著活化,而在SHEE细胞中未见活化Src激酶。Dasatinib可显著抑制KYSE180细胞增殖,阻碍细胞G1/S期转换,促进细胞凋亡,并上调caspase3、cytochrome C和Bax等凋亡相关蛋白的表达。另外,dasatinib可显著抑制裸鼠皮下KYSE180细胞移植瘤的生长。结论:Dasatinib可通过抑制食管鳞癌细胞增殖、促进细胞凋亡以及影响细胞周期等机制,抑制食管鳞癌细胞皮下移植瘤的生长,因此其可望成为治疗食管鳞癌的一个有效药物。Objective： To investigate the effects of Src tyrosine kinase inhibitor dasatinib on the cell proliferation and apoptosis of human esophageal squamous cell carcinoma and the related mechanism. Methods： Western blotting was used to detect the expressions of total Src and phos-Src tyrosine kinase in esophageal squamous-cell cancer cell lines KYSE180, EC109 and KYSE30 as well as human immortalized esophageal epithelial cell line SHEE. The inhibition effect of different concentrations of Src tyrosine kinase inhibitor dasatinib on Src kinase and the effects of dasatinib on proliferation, cell-cycle and apoptosis of KYSE180 cells as well as the growth of subcutaneous xenograft of KYSE180 cells in nude mice were examined by MTT method, flow cytometry （FCM）, Western blotting and an experimental xenograft mouse model. Results： The activation level of Src tyrosine kinase was significantly increased in KYSE180, EC109 and KYSE30 cells, and this effect was not observed in SHEE cells. Dasatinib could significantly inhibit the proliferation of KYSE180 cells, and also inhibit G1/S transition, induce apoptosis and upregulate the expression levels of apoptosis-related caspase 3, cytochrome C and Bax proteins in KYSE180 cells. Furthermore, the growth of subcutaneous xenograft of KYSE180 cells in nude mice was obviously inhibited by dasatinib treatment. Conclusion： Dasatinib can inhibit the growth of subcutaneous xenograft of KYSE180 cells in nude mice by inhibiting cell proliferation, inducing apoptosis and influencing the distribution of cell cycle, and it may be considered as an effective agent for the treatment of esophageal squamous cell carcinoma.

关 键 词：食管肿瘤 Src族激酶类 蛋白激酶抑制剂 细胞增殖 细胞凋亡 细胞周期 基因表达 DASATINIB 

分 类 号：R735.1[医药卫生—肿瘤]