Protein phosphatase 2A is required for mesalazine-dependent inhibition of Wnt/beta-catenin pathway activity.
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/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 adenomatous polyposis coli 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, using concentrations of mesalazine identical to concentrations seen in patients with inflammatory bowel disease, that mesalazine inhibits the Wnt/beta-catenin pathway via inhibition of PP2A.
Bos
Carina L
CL
Laboratory of Experimental Oncology and Radiobiology, Department of Oncology, University of Amsterdam, The Netherlands. carinaenjeroen@wanadoo.nl
Diks
Sander H
SH
Hardwick
James C H
JC
Walburg
Kimberley V
KV
Peppelenbosch
Maikel P
MP
Richel
Dick J
DJ
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000188:drug therapy; D003110:Colonic Neoplasms; D015179:Colorectal Neoplasms / Q000517:prevention & control; D006801:Humans; D007700:Kinetics; D019804:Mesalamine / Q000494:pharmacology* / Q000627:therapeutic use; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D051176:beta Catenin / Q000037:antagonists & inhibitors*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051153:Wnt Proteins; D051176:beta Catenin; D019804:Mesalamine; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2