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.

• Authors: Chengcheng You, Shimin Zhang, Yingming Sun, Shiyu Zhang, Guiliang Tang, Fang Tang, Xuefeng Liu, Yu Xiao, Junhong Zhang, Yan Gong, Conghua Xie
• Journal: International journal of oncology (Int J Oncol) Vol. 53 Issue 5 Pg. 2258-2268 (Nov 2018) ISSN: 1791-2423 [Electronic] Greece
• PMID: 30132512 (Publication Type: Journal Article)

Chemical References

• CTNNB1 protein, human
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10A protein, human
• TNFRSF10B protein, human
• beta Catenin

Topics

• Apoptosis (drug effects, genetics)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, physiology)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• beta Catenin (genetics, metabolism)