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Background  The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of β-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E 2  (PGE 2 ) - PI-3 kinase pathways. Recent reports show that PGE 2 -induced phosphorylation of β-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE 2  on β-catenin homeostasis.    Findings  Treatment of  Apc  Min/+  mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of β-catenin, β-catenin nuclear translocation and expression of the β-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE 2 -induced β-catenin phosphorylation and c-Myc upregulation.    Conclusion  Based on our findings we suggest that PGE 2  act through PKA to promote β-catenin nuclear translocation and tumor development in  Apc  Min/+  mice  in vivo , indicating that the direct regulatory effect of PKA on β-catenin nuclear translocation is operative in intestinal cancer.

Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in ApcMin/+ mice