β-catenin decreases acquired TRAIL resistance in non-small-cell lung cancer cells by regulating the redistribution of death receptors

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits antitumor activity in various types of tumor cell and tumor-bearing animals. However, acquired TRAIL resistance is a common issue that restricts its clinical application. Previous studies have revealed that β-catenin is associated with TRAIL resistance in melanoma and colorectal tumors. In the present study, an acquired-resistance non-small-cell lung cancer (NSCLC) cell line (H460-TR) was established from parental TRAIL-sensitive H460 cells using a gradient ascent model (8-256 ng/ml TRAIL). Cellular FADD-like interleukin-1β converting enzyme inhibitory protein and Mcl-1 were upregulated and the cell surface distribution of death receptor (DR)4 and DR5 was downregulated in H460-TR cells compared with the parental H460 cells. The results of reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that H460 cells expressed increased levels of β-catenin and were more sensitive to TRAIL compared with H460-TR cells. β-catenin-knockdown in H460 cells decreased their sensitivity to TRAIL, while upregulation of β-catenin expression in H460-TR cells increased their sensitivity to TRAIL, increased the cell surface distribution of DRs and activated caspase-3/8. Taken together, the results of the present study suggest that β-catenin impairs acquired TRAIL resistance in NSCLC cells by promoting the redistribution of DR4 and DR5 to the cytomembrane, and inducing TRAIL-mediated cell apoptosis via caspase-3/8 activation.