肝X受体激动剂GW3965对人结肠癌细胞奥沙利铂耐药的逆转作用及机制  

Reversal effect of liver X receptor agonist GW3965 on oxaliplatin resistance in human colon cancer cells and its mechanism

作　　者：谭湘洲 王然[1] 文俏程[1] 莫砚群 吴瑞平 陈志康[1] 

机构地区：[1]中南大学湘雅医院结直肠肛门外科,湖南长沙410008

出　　处：《中国普通外科杂志》2017年第10期1258-1264,共7页China Journal of General Surgery

基　　金：国家自然科学基金资助项目(81573012)

摘　　要：目的:探讨肝X受体(LXR)激动剂GW3965对人结肠癌细胞奥沙利铂(OXA)耐药的逆转作用及机制。方法:用OXA药物浓度持续递增法诱导人结肠癌HCT116细胞构建OXA耐药的人结肠癌HCT116/L-OHP细胞,比较HCT116/L-OHP细胞与其亲本HCT116细胞的生长情况,以及对不同浓度OXA作用的反应情况;检测HCT116/L-OHP细胞经GW3965处理48 h后OXA耐药性及自噬相关蛋白ATG-5、Beclin-1、p62、LC3的表达的变化。结果:成功构建人结肠癌耐OXA细胞HCT116/L-OHP,表现为HCT116/L-OHP细胞与亲本HCT116细胞比较,增殖能力有所减弱,但对OXA的耐药性明显增强(IC_(50):244.99μmol/L vs.10.05μmol/L,P<0.05),其耐药指数(RI)为24.45。不同浓度(10、20、30μmol/L)GW3965作用后,HCT116/L-OHP细胞对OXA的IC_(50)、RI均明显降低(均P<0.05),且呈浓度依赖性(IC_(50):199.49、114.71、87.32μmol/L;RI:19.89、11.40、8.69),3个浓度的逆转倍数分别为1.23、2.15、2.82;ATG-5、Beclin-1蛋白的表达明显降低,而p62、LC3-II蛋白的表达明显升高(均P<0.05),且均呈浓度依赖性。结论:LXR激动剂GW3965可逆转人结肠癌细胞对OXA的耐药,其机制可能与调节自噬相关蛋白表达水平有关。Objective： To investigate the reversal effect of liver X receptor （LXR） agonist GW3965 on oxaliplatin （OXA） resistance in human colon cancer cells and its mechanism. Methods： OXA-resistant human colon cancer HCT116/L-OHP cells were established by stepwise exposure of human colon cancer HCT116 cells to increasing concentrations of OXA. The growth abilities and responses to OXA treatment between HCT116/L-OHP cells and their parent HCT116 cells were compared; the changes in OXA resistance and expressions of autophagy-related protein ATG-5, Beclin-1, p62 and LC3 in HCT- 116/L-OHP ceils after exposure to GW3965 for 48 h were determined. Results： The OXA-resistant HCT116/L-OHP cells were successfully established, as evidenced by the slightly decreased proliferative ability but significantly increased resistance to OXA in HCT 116/L-OHP cells compared with their parent HCT116 cells （IC50：244.99 ~mol/L vs. 10.05 ~tmol/L, P〈0.05）, with a resistance index （RI） of 24.45. In HCT116/L-OHP cells after exposure to different concentrations （10, 20 and 30 [trnol/L） of GW3965, the ICs0 and RI to OXA were significantly decreased （all P〈0.05）, with a concentration-dependent manner （ICs0： 199.49, 114.71 and 87.32 tmaol/L; RI： 19.89, 11.40 and 8.69）, and the reversal fold for the three concentrations was 1.23, 2.15 and 2.82 respectively; the expression levels of ATG-5 and Beclin-1 protein were significantly decreased, while the expression levels of p62 and LC3-II were significantly increased （all P〈0.05）, which all showed a concentration-dependent profile. Conclusion： LXR agonist GW3965 can reverse OXA resistance in human colon cancer ceils, and the mechanism may be associated with its regulating the expression levels of the autophagy-related proteins.

关 键 词：结肠肿瘤 抗药性 肿瘤 孤儿核受体 自噬 

分 类 号：R735.3[医药卫生—肿瘤]