Inhibitory effects of XAV939 on the proliferation of small-cell lung cancer H446 cells and Wnt/β-catenin signaling pathway in vitro

摘要

Lung cancer, including small-cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), are the most common tumor types, which represent 13% of newly diagnosed cancer cases worldwide. SCLC represents 15% of all lung cancer cases. Although an increasing number of novel targeted drugs are employed for the treatment of NSCLC, including Iressa, Tarceva and Conmana, there have been almost no major breakthroughs in SCLC over the last 30 years. Therefore, new drug targets are required to treat or prevent SCLC. Aberrant Wnt signaling is associated with numerous types of tumors, and it plays a key role in cell proliferation and survival. Recent preclinical studies suggested that XAV939 is a small-molecule inhibitor of the Wnt signaling pathway. In the present study, whether XAV939 is able to inhibit the proliferation of SCLC cells and the underlying mechanism were investigated. The inhibition of cell proliferation was detected by Cell Counting Kit-8 (CCK-8) assay. The mRNA expression of β-catenin and cyclin D1 were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and the protein expression of β-catenin and cyclin D1 was determined by western blotting. The results from the CCK-8 cell viability assay confirmed that XAV939 is able to inhibit the proliferation of SCLC cells in a dose-dependent manner. However, the effects of XAV939 were not time-dependent. By contrast, the effect of DDP treatment was time- and dose-dependent. Furthermore, the effect of combination treatment with XAV939 and DDP was antagonistic at low doses and synergistic at high doses. It was also observed that the mRNA and protein expression of β-catenin and cyclin D1 was significantly in SCLC cells following XAV939 treatment compared with the control group. These findings suggested that XAV939 is able to inhibit the proliferation of H446 cells, at least partially, through downregulating the Wnt/β-catenin signaling pathway. All of these results may provide potential therapeutic approaches for the treatment of SCLC.