Overexpression of the beta-catenin binding domain of cadherin selectively kills colorectal cancer cells.
The beta-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 beta-catenin/Tcf4 transcriptional activity, as determined by results from microarray experiments. Our results support the view that beta-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.
Pierce
Michael
M
Deltagen Proteomics, Salt Lake City, UT, USA.
Wang
Chunwei
C
Stump
Mark
M
Kamb
Alexander
A
D015703:Antigens, CD; D017209:Apoptosis; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion; D002455:Cell Division; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D051176:beta Catenin; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D000099152:Cadherin 5; C495270:CTNNB1 protein, human; C544894:TCF7L2 protein, human