Regulation of TRAIL receptor expression by β-catenin in colorectal tumours.

Abstract

Tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is being investigated as a targeted cancer therapeutic and the expression of its pro-apoptotic receptors, DR4 and DR5, increases during colorectal carcinogenesis. This study investigated the role of β-catenin in the regulation of these receptors. In human colorectal adenoma and carcinoma cell lines, downregulation of β-catenin resulted in lower total DR4 and DR5 protein levels. Similarly, cell membrane expression of DR4 and DR5 was reduced after downregulation of β-catenin in colon carcinoma cells, whereas induction of β-catenin in HeLa cells led to increased cell membrane expression of DR4 and DR5. Downregulation of β-catenin decreased the recombinant human TRAIL sensitivity of human colon carcinoma cells. Activation of the transcription factor T-cell factor-4 (TCF-4) is an important function of β-catenin. Dominant-negative TCF-4 overexpression, however, did not significantly affect TRAIL receptor expression or recombinant human TRAIL sensitivity. Human colorectal adenomas (N = 158) with aberrant (cytoplasmic and nuclear) β-catenin expression had a higher percentage of immunohistochemical DR4 and DR5 staining per tumour (mean: 73 and 88%, respectively) than those with membranous β-catenin staining only (mean: 50 and 70%, respectively, P < 0.01 for both). Furthermore, aberrant β-catenin staining co-localized with DR4 and DR5 expression in 92% of adenomas. In 53 human colorectal carcinomas, aberrant β-catenin expression was present in most cases and DR4/5 expression was largely homogenous. Similarly, in adenomas from APC(min) mice, cytoplasmic β-catenin staining co-localized with staining for the murine TRAIL death receptor. In conclusion, the gradual increase in TRAIL receptor expression during colorectal carcinogenesis is at least partially mediated through increased β-catenin expression, independently of TCF-4-signalling.

• Authors: M Jalving, D M Heijink, J J Koornstra, W Boersma-van Ek, N Zwart, J Wesseling, W J Sluiter, E G E de Vries, J H Kleibeuker, S de Jong
• Journal: Carcinogenesis (Carcinogenesis) Vol. 35 Issue 5 Pg. 1092-9 (May 2014) ISSN: 1460-2180 [Electronic] England
• PMID: 24379239 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• beta Catenin

Topics

• Adenoma (genetics, metabolism, pathology)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Carcinoma (genetics, metabolism, pathology)
• Cell Line, Tumor
• Child
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Down-Regulation (genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Middle Aged
• Neoplasm Grading
• Neoplasm Staging
• Protein Binding
• Protein Transport
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• TNF-Related Apoptosis-Inducing Ligand (metabolism, pharmacology)
• Tumor Burden
• Young Adult
• beta Catenin (genetics, metabolism)