Protein kinase A antagonist inhibits ?-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice.

ABSTRACT: BACKGROUND: The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of ?-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 ?-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE(2) on ?-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 ?-catenin, ?-catenin nuclear translocation and expression of the ?-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 ?-catenin phosphorylation and c-Myc upregulation. CONCLUSION: Based on our findings we suggest that PGE(2) act through PKA to promote ?-catenin nuclear translocation and tumor development in Apc(Min/+) mice in vivo, indicating that the direct regulatory effect of PKA on ?-catenin nuclear translocation is operative in intestinal cancer.

SUBMITTER: Brudvik KW 

PROVIDER: S-EPMC3278393 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature