Effect of nonsteroidal anti-inflammatory drugs on β-catenin protein levels and catenin-related transcription in human colorectal cancer cells

Abstract

Elevated b-catenin levels in human colorectal cancer (CRC) cells lead to increased trans-activation of 'protumorigenic' b-catenin/Tcell factor (TCF) target genes such as cyclin D1. Therefore, possible targets for the anti-CRC activity of nonsteroidal anti-inflammatory drugs (NSAIDs) are b-catenin and catenin-related transcription (CRT). We tested the antiproliferative activity and the effects on levels of b-catenin and cyclin D1 protein, as well as CRT (measured using a synthetic b-catenin/TCF-reporter gene [TOPflash]), of a panel of NSAIDs (indomethacin, diclofenac, sulindac sulphide and sulphone, rofecoxib; range 10 -600 mM) 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 b-catenin protein levels or CRT. All the NSAIDs, except rofecoxib, decreased nuclear b-catenin content and cyclin D1 protein levels in parallel with their antiproliferative activity. However, cyclin D1 downregulation occurred prior to a decrease in total b-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 b-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.

The proapoptotic effects of sulindac, sulindac sulfone and indomethacin are mediated by nucleolar translocation of the RelA(p65) subunit of NF-κB

“…It is now of extreme interest, to define the pathways upstream of NF-kB that are activated by these different agents. We and others have identified p38-mediated degradation of cyclinD1/inhibition of CDK4 as particularly interesting in this regard (Gardner et al, 2004;Sun and Sinicrope, 2005;Thoms et al, 2007).…”

Repression of β-catenin function in malignant cells by nonsteroidal antiinflammatory drugs

“…Hence, it is logical to assume that NSAIDs inhibit ␤-catenin function in some way. Indeed, reduced nuclear expression of ␤-catenin has been observed in some colonic polyps from patients treated with an NSAID (30)(31)(32). However, the clinical observations have been difficult to explain at a molecular level.…”

“…Moreover, the colonic polyps of patients treated with NSAIDs have reduced nuclear accumulation of ␤-catenin (29). The biochemical and clinical data imply that NSAIDs inhibit ␤-catenin activity or its stability (31,32). However, the biochemical basis for these effects is uncertain, insofar as NSAIDs have not been shown to interact directly with ␤-catenin.…”

“…Different NSAIDs have been demonstrated to inhibit the activity of ␤-catenin-dependent reporter genes in malignant cell lines, and to induce ␤-catenin degradation (29)(30)(31)(32)(33)(34). Moreover, the colonic polyps of patients treated with NSAIDs have reduced nuclear accumulation of ␤-catenin (29).…”

A direct protein-protein interaction is involved in the suppression of β-catenin transcription by retinoid X receptor α in colorectal cancer cells

“…9 Oncogenic activation of the Wnt-signaling pathway by mutations in Adenomatous polyposis coli (APC) or β-catenin, which results in the accumulation and nuclear translocation of β-catenin and in β-catenin/T-cell factor (TCF) 4-regulated transcription of TCF target genes such as cyclin D1 and c-MYC, is mandatory for the initial neoplastic transformation of intestinal epithelium. 10 Therefore, targeting β-catenin is a promising strategy for cancer prevention and chemotherapy via suppressing β-catenin by nonsteroidal anti-inflammatory drugs (NSAIDs), [11][12][13][14] which required high level expression of PPARγ and RXRα. 15 It has been reported that RAR interacts with β-catenin and inhibits β-catenin-mediated gene transcription.…”