Overexpression of the β-catenin binding domain of cadherin selectively kills colorectal cancer cells

Abstract

The β-catenin pathway is involved in growth, differentiation and tumor formation. Suppression of pathway activity by expressed inhibitors can cause growth arrest or apoptosis in certain colon carcinoma lines. We compare the effects of 2 pathway inhibitors, a VE-cadherin cytoplasmic domain fragment (Cad5CD) and a truncated, dominant-negative Tcf4 (TcfDN), using a microplate assay for cell death and microarray gene expression analysis. The cell-lethal assay shows that Cad5CD, when expressed in HT29 human colon tumor cells and 3 non-colon lines, selectively kills the HT29 cells. Cad5CD overexpression inhibits β-catenin/Tcf4 transcriptional activity, as determined by results from microarray experiments. Our results support the view that β-catenin is an attractive anti-cancer target, especially if the Cad5CD binding site or Cad5CD itself can be exploited for drug development. In addition, therapeutically relevant phenotypes such as drug selectivity may be difficult to predict from gene expression analysis alone. Other more specialized phenotypic tests such as cell-lethal assays may be required. © 2003 Wiley-Liss, Inc.