Interference with the expression of β-catenin reverses cisplatin resistance in A2780/DDP cells and inhibits the progression of ovarian cancer in mouse model.

Abstract

Cisplatin is a most active drug for the treatment of ovarian cancer; however, acquired cisplatin resistance is easily seen in patients with ovarian cancer. The aim of this study is to clarify the molecular mechanism of cisplatin resistance and try to reverse cisplatin resistance in ovarian cancer lines in vitro and in vivo. First, we used ovarian cancer cell line A2780, and its cisplatin-resistant subline, A2780/DDP as cell model. Cell viability was determined by MTT assay and the IC50 values were observed to increase in a dose- and time-dependent manner. Next, the expression of β-catenin was determined by western blotting analysis, and the results demonstrated that the expression level of β-catenin in A2780/DDP cells was significantly higher than that in A2780 cells (p<0.01). Moreover, we detected the distribution of cytoplasmic and nuclear β-catenin by western blot analysis, which showed that β-catenin was mainly located in nucleus. Compared with A2780 cells, there was no obvious change as the increasing dose of cisplatin in A2780/DDP cells reveal that cisplatin resistance was related to the exrpession of β-catenin. Furthermore, interference with the expression of β-catenin could effectively reverse cisplatin resistance as IC50 was significantly decreased from 123.7 to 42.43 μM in A2780/DDP cells. Additionally, transient interference of β-catenin by siRNA promoted the apoptosis of A2780/DDP cells, for increased apoptosis rates and cleaved caspase-3 levels were detected being treated with cisplatin. Finally, tumorigenicity experiments showed that tumor growth was significantly suppressed in β-catenin shRNA group. The body weight was not significantly changed during the experimental days. In conclusion, all the results showed that cisplatin resistance was partly induced by Wnt/β-catenin signaling pathway. Interfering the expression of β-catenin could reverse cisplatin resistance in vitro and in vivo. Thus, β-catenin could be a potential therapeutic target for the therapy of cisplatin-resistant ovarian cancer.