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
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.