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Mol Cancer. 2011 Dec 15;10:149. doi: 10.1186/1476-4598-10-149.

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

Author information

1
Centre for Molecular Medicine Norway, Nordic EMBL Partnership and Biotechnology Centre, University of Oslo, Oslo, Norway.

Abstract

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.

PMID:
22168384
PMCID:
PMC3278393
DOI:
10.1186/1476-4598-10-149
[Indexed for MEDLINE]
Free PMC Article

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