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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。
AIM: To investigate the reversal effect of ox-LDL (OXA) on human colorectal cancer cells induced by hepatic X receptor (LXR) agonist GW3965 and its mechanism. Methods: OXA-resistant human colon cancer HCT116 / L-OHP cells were induced by continuous increasing concentration of OXA in human colon cancer HCT116 cells. The growth of HCT116 / L-OHP cells and their parental HCT116 cells were compared, and the effects of different concentrations of OXA The changes of OXA resistance, the expression of autophagy-related proteins ATG-5, Beclin-1, p62 and LC3 in HCT116 / L-OHP cells treated with GW3965 for 48 h were detected. RESULTS: HCT116 / L-OHP was successfully constructed in human colon cancer resistant OXA cells. Compared with HCT116 cells, the proliferation of HCT116 / L-OHP cells was reduced, but the drug resistance to OXA was significantly increased (IC 50, : 244.99 μmol / L vs. 10.05 μmol / L, P <0.05). The resistance index (RI) was 24.45. The IC50 and RI of HCT116 / L-OHP cells were significantly decreased (all P <0.05) in a concentration dependent manner (IC 50) after treated with different concentrations of GW3965 (10, 20 and 30μmol / : 199.49,114.71,87.32μmol / L, RI: 19.89,11.40,8.69). The reversal multiples of three concentrations were 1.23,2.15,2.82 respectively. The expression of ATG-5 and Beclin-1 protein was significantly decreased, while the expression of p62 and LC3 -II protein expression was significantly increased (all P <0.05), and all in a concentration-dependent manner. CONCLUSION: LXR agonist GW3965 can reverse the drug resistance of human colon cancer cells to OXA. The mechanism may be related to the regulation of autophagy-related protein expression.