Effect of nonsteroidal anti-inflammatory drugs on beta-catenin protein levels and catenin-related transcription in human colorectal cancer cells.
Elevated beta-catenin levels in human colorectal cancer (CRC) cells lead to increased trans-activation of 'protumorigenic' beta-catenin/T-cell factor (TCF) target genes such as cyclin D1. Therefore, possible targets for the anti-CRC activity of nonsteroidal anti-inflammatory drugs (NSAIDs) are beta-catenin and catenin-related transcription (CRT). We tested the antiproliferative activity and the effects on levels of beta-catenin and cyclin D1 protein, as well as CRT (measured using a synthetic beta-catenin/TCF-reporter gene [TOPflash]), of a panel of NSAIDs (indomethacin, diclofenac, sulindac sulphide and sulphone, rofecoxib; range 10-600 microM) on SW480 human CRC cells in vitro. Following NSAID treatment, there was no consistent relationship between reduced cell proliferation, induction of apoptosis and changes in beta-catenin protein levels or CRT. All the NSAIDs, except rofecoxib, decreased nuclear beta-catenin content and cyclin D1 protein levels in parallel with their antiproliferative activity. However, cyclin D1 downregulation occurred prior to a decrease in total beta-catenin protein levels and there was no correlation with changes in CRT, suggesting the existence of CRT-independent effects of NSAIDs on cyclin D1 expression. In summary, NSAIDs have differential effects on beta-catenin protein and CRT, which are unlikely to fully explain their effects on cyclin D1 and their antiproliferative activity on human CRC cells in vitro. British Journal of Cancer (2004) 91, 153-163. doi:10.1038/sj.bjc.6601901 www.bjcancer.com Published online 8 June 2004
Gardner
S H
SH
Molecular Medicine Unit, University of Leeds, St James's University Hospital, Leeds LS9 7TF, UK.
Hawcroft
G
G
Hull
M A
MA
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology*; D019938:Cyclin D1 / Q000096:biosynthesis*; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D015536:Down-Regulation; D006801:Humans; D015534:Trans-Activators / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1