Journal Article

Indomethacin induces differential expression of β-catenin, γ-catenin and T-cell factor target genes in human colorectal cancer cells

Gillian Hawcroft, Mark D'Amico, Chris Albanese, Alexander F. Markham, Richard G. Pestell and Mark A. Hull

in Carcinogenesis

Volume 23, issue 1, pages 107-114
Published in print January 2002 | ISSN: 0143-3334
Published online January 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.1.107
Indomethacin induces differential expression of β-catenin, γ-catenin and T-cell factor target genes in human colorectal cancer cells

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Indomethacin-induced G1 arrest and apoptosis of human colorectal cancer (CRC) cells is associated with a dose-dependent decrease in β-catenin protein levels. β-catenin plays a pivotal role in the WNT signalling pathway and its expression is frequently dysregulated at early stages of colorectal carcinogenesis. The objective of this study was to investigate the effect of indomethacin on catenin expression and downstream WNT signalling events in human CRC cells. β-catenin, γ-catenin and T-cell facter (TCF) target gene (cyclin D1, c-MYC and PPARδ) expression was studied following indomethacin treatment of SW480 and HCT116 cells. Cyclin D1 was used as a model TCF target gene for analysis of β-catenin–TCF-4 DNA binding and trans-activation. Indomethacin treatment was associated with a specific decrease in β-catenin (but not γ-catenin) expression. Resulting TCF target gene expression was gene specific (cyclin D1, decreased; c-MYC, increased; PPARδ, no significant change). Cyclin D1 promoter analysis revealed that indomethacin disrupted formation of a β-catenin–TCF-4–DNA complex. Indomethacin-induced G1 arrest and apoptosis is associated with specific β-catenin down-regulation in human CRC cells in vitro. Differential expression of TCF target genes following indomethacin treatment implies complex effects on multiple genes which play an important role in colorectal carcinogenesis.

Keywords: APC, adenomatous polyposis coli; COX, cyclooxygenase; CRC, colorectal cancer; CREB, cAMP-responsive element binding protein; CTNNB1, human β-catenin gene; EMSA, electromobility shift assay; FAP, familial adenomatous polyposis; G6PDH, glucose-6-phosphate dehydrogenase; GSK, glycogen synthase kinase; NSAIDs, non-steroidal anti-inflammatory drugs; PPAR, peroxisome proliferator-activated receptor; PK, protein kinase; TCF, T-cell factor; TK, thymidine kinase; WISP-1, WNT-1 induced secreted protein 1.

Journal Article.  5722 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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