CDH17 facilitates β-catenin nuclear translocation to reduce drug sensitivity in cisplatin-resistant gastric cancer cells

Meng Liu, Zheng Han, Ziqiang Zhong, Jie Tan, Qingxi Zhu, Wei Chen, Shasha Huang, Xiaoli Chen,  Xia Tian

Abstract:

Chemoresistance greatly impairs the effectiveness of chemotherapy in gastric cancer (GC) patients. According to our prior results, Cadherin-17 (CDH17) contributes to chemoresistance in GC through activating the Wnt/β-catenin pathway; however, its specific molecular mechanisms require further elucidation. We compared the Wnt/β-catenin pathway activation levels between cisplatin (DDP)-resistant GC cell lines and their parental cell lines. Subsequently, we carried out loss-of-function and gain-of-function tests to investigate CDH17 for its effect on regulating β-catenin expression, nuclear transport, as well as transcriptional activity within DDP-resistant GC cells. Additionally, CDH17 was examined for its role in the expression of four ABC transporters using molecular assays. Finally, rescue experiments were carried out using the Wnt signaling pathway agonist CP21R7 and inhibitor IWR-1 to elucidate the specific mechanism of CDH17 in promoting chemotherapy resistance of GC cells. The results showed that the activation level of the Wnt/β-catenin signaling pathway was significantly elevated in DDP-resistant GC cell lines compared to their parental cell lines. Silencing CDH17 resulted in reduced expression, impaired nuclear translocation, and decreased transcriptional activity of β-catenin, whereas overexpression of CDH17 had the opposite effects. Notably, CDH17 was shown to specifically regulate the expression of ABCB1 (protein name: P-glycoprotein, P-gp) in resistant cells, with no observable impact on the other three ABC transporters (ABCC1, ABCG2, and ABCC2) examined. Importantly, treatment with IWR-1 effectively reversed the enhancing effect of CDH17 overexpression on P-gp protein expression, as well as its suppressive effects on DDP accumulation and chemosensitivity. Conversely, administration of CP21R7 attenuated the inhibitory consequences of CDH17 silencing on P-gp expression, DDP efflux, and drug resistance. In conclusion, CDH17 promotes the expression and nuclear translocation of β-catenin in GC cells, leading to activation of the Wnt/β-catenin signaling pathway, which subsequently upregulates ABCB1/P-gp expression and enhances cellular capacity for DDP efflux. These findings imply that targeting CDH17 could be a potential strategy for overcoming chemotherapy resistance in GC.