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Carcinogenesis Advance Access published online on May 25, 2006
Carcinogenesis, doi:10.1093/carcin/bgl071
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received November 17, 2005
Revised March 28, 2006
Accepted May 5, 2006

CANCER BIOLOGY

Protein phosphatase 2A is required for mesalazine-dependent inhibition of Wnt/{beta}-catenin pathway activity

Carina L. Bos 1 *, Sander H. Diks 2, James C. H. Hardwick 3, Kimberley V. Walburg 3, Maikel P. Peppelenbosch 2, and Dick J. Richel 4

1 Laboratory of Experimental Oncology and Radiobiology, University of Amsterdam, The Netherlands; Department of Oncology, University of Amsterdam, The Netherlands
2 Department of Cell Biology, University of Groningen, The Netherlands
3 Laboratory of Experimental Oncology and Radiobiology, University of Amsterdam, The Netherlands
4 Department of Oncology, University of Amsterdam, The Netherlands

* To whom correspondence should be addressed.
Carina L. Bos, E-mail: carinaenjeroen{at}wanadoo.nl


  Abstract

The rising incidence and poor prognosis of colorectal cancer have aroused substantial interest in novel chemopreventive strategies. Interestingly, treatment of ulcerative colitis with mesalazine, which displays few side effects during long-term treatment, is associated with a reduced incidence of colorectal cancer, but its molecular mechanism is unknown. The effect of mesalazine on the Wnt/{beta}-catenin pathway was studied in colorectal cancer cell lines to find a molecular basis underlying its chemopreventive features. Mesalazine affects the Wnt/{beta}-catenin pathway in APC mutated cells with intact {beta}-catenin, judged by luciferase reporter assays. Furthermore, mesalazine treatment reduced expression of nuclear {beta}-catenin and Wnt/{beta}-catenin target genes, and increased {beta}-catenin phosphorylation. This effect on the Wnt/{beta}-catenin pathway is mediated via protein phosphatase 2A (PP2A): increased phosphorylation of PP2A after mesalazine treatment is observed, which coincides with decreased PP2A enzymatic activity. The inhibition of PP2A enzymatic activity by mesalazine is essential for its effect on the Wnt/{beta}-catenin pathway, as shown by transient transfection with siPP2A and mutant PP2A. This study shows that using concentrations of mesalazine identical to concentrations seen in patients with inflammatory bowel disease (IBD), mesalazine inhibits the Wnt/{beta}-catenin pathway via inhibition of PP2A.

Keywords: Mesalazine; Colon Cancer; Wnt/{beta}-catenin pathway; PP2A.
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