Journal Article

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

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

in Carcinogenesis

Volume 27, issue 12, pages 2371-2382
ISSN: 0143-3334
Published online May 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl071
Protein phosphatase 2A is required for mesalazine-dependent inhibition of Wnt/β-catenin pathway activity

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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 not known. The effect of mesalazine on the Wnt/β-catenin pathway was studied in colorectal cancer cell lines to find a molecular basis underlying its chemopreventive features. Mesalazine affects the Wnt/β-catenin pathway in adenomatous polyposis coli mutated cells with intact β-catenin, judged by luciferase reporter assays. Furthermore, mesalazine treatment reduced expression of nuclear β-catenin and Wnt/β-catenin target genes, and increased β-catenin phosphorylation. This effect on the Wnt/β-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/β-catenin pathway, as shown by transient transfection with siPP2A and mutant PP2A. This study shows, using concentrations of mesalazine identical to concentrations seen in patients with inflammatory bowel disease, that mesalazine inhibits the Wnt/β-catenin pathway via inhibition of PP2A.

Journal Article.  7354 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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