Positive Health Online

Abstract

DILLARD and  LANE, Department of Human Ecology, Division of Nutritional Sciences, The University of Texas at Austin, Austin, Texas 78712, USA studied the regulation of the beta-catenin signalling pathway in colon cancer in human colon cancer cell lines.

Background

The authors note that beta-catenin signaling pathway is dysregulated in most cases of colon cancer, resulting in an accumulation of nuclear beta-catenin and increased transcription of genes involved in tumour progression.

Methodology

The authors examined the effect of retinol on beta-catenin protein levels in three all-trans retinoic acid (ATRA)-resistant human colon cancer cell lines: HCT-116, WiDr, and SW620. Each cell line was treated with increasing concentrations of retinol for 24 or 48 h.

Results

Retinol reduced beta-catenin protein levels and increased ubiquitinated beta-catenin in all cell lines. Treatment with the proteasomal inhibitor MG132 blocked the retinol-induced decrease in beta-catenin, indicating retinol decreases beta-catenin by increasing proteasomal degradation. Multiple pathways direct beta-catenin to the proteasome for degradation including a p53/Siah-1/adenomatous polyposis coli (APC), a Wnt/glycogen synthase kinase-3beta/APC, and a retinoid 'X' receptor (RXR)-mediated pathway. Due to mutations in beta-catenin (HCT-116), APC (SW620), and p53 (WiDr), only the RXR-mediated pathway remains functional in each cell line. To determine if RXRs facilitate beta-catenin degradation, cells were treated with the RXR pan-antagonist, PA452, or transfected with RXRalpha small interfering RNA (siRNA). The RXR pan-antagonist and RXRalpha siRNA reduced the ability of retinol to decrease beta-catenin protein levels. Nuclear beta-catenin induces gene transcription via interaction with T cell factor/lymphoid enhancer factor (TCF/LEF) proteins. Retinol treatment decreased the transcription of a TOPFlash reporter construct and mRNA levels of the endogenous beta-catenin target genes, cyclin D1 and c-myc.

Conclusion

These results indicate that retinol may reduce colon cancer cell growth by increasing the proteasomal degradation of beta-catenin via a mechanism potentially involving a retinoid 'X' receptor (RXR).

References

Dillard AC and  Lane MA. Retinol decreases beta-catenin protein levels in retinoic acid-resistant colon cancer cell lines. Molecular Carcinogenesis.  46(4):315-29 Apr 2007.