基础研究(Basic Research)

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

Published at: 2017年第26卷第10期

谭湘洲 1 , 王然 1 , 文俏程 1 , 莫砚群 1 , 吴瑞平 1 , 陈志康 1
1 中南大学湘雅医院 结直肠肛门外科,湖南 长沙 410008
通讯作者 志康 陈 Email: chenzk1974@hotmail.com
DOI: 10.3978/j.issn.1005-6947.2017.10.006
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(IC50:244.99 µmol/L vs. 10.05 µmol/L,P<0.05),其耐药指数(RI)为24.45。不同浓度(10、20、30 µmol/L)GW3965作用后,HCT116/L-OHP细胞对OXA的IC50、RI均明显降低(均P<0.05),且呈浓度依赖性(IC50:199.49、114.71、87.32 µmol/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。


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

Abstract

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 cells 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 HCT116/L-OHP cells compared with their parent HCT116 cells (IC50: 244.99 µmol/L vs. 10.05 µmol/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 µmol/L) of GW3965, the IC50 and RI to OXA were significantly decreased (all P<0.05), with a concentration-dependent manner (IC50: 199.49, 114.71 and 87.32 µmol/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 cells, and the mechanism may be associated with its regulating the expression levels of the autophagy-related proteins.


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引用

引用本文: 湘洲 谭, 然 王, 俏程 文, 砚群 莫, 瑞平 吴, 志康 陈. 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[J]. 中国普通外科杂志, 2017, 26(10): 1258-1264.
Cite this article as: TAN Xiangzhou, WANG Ran, WEN Qiaocheng, MO Yanqun, WU Ruiping, CHEN Zhikang . Reversal effect of liver X receptor agonist GW3965 on oxaliplatin resistance in human colon cancer cells and its mechanism[J]. Chin J Gen Surg, 2017, 26(10): 1258-1264.