Protein kinase A antagonist inhibits β-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 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.

• Authors: Kristoffer W Brudvik, Jan E Paulsen, Einar M Aandahl, Borghild Roald, Kjetil Taskén
• Journal: Molecular cancer (Mol Cancer) Vol. 10 Pg. 149 (Dec 15 2011) ISSN: 1476-4598 [Electronic] England
• PMID: 22168384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 8-bromoadenosine-3',5'-cyclic monophosphorothioate
• Adenomatous Polyposis Coli Protein
• Myc protein, mouse
• Proto-Oncogene Proteins c-myc
• Thionucleotides
• beta Catenin
• 8-Bromo Cyclic Adenosine Monophosphate
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Cyclic AMP-Dependent Protein Kinases

Topics

• 8-Bromo Cyclic Adenosine Monophosphate (analogs & derivatives, pharmacology)
• Active Transport, Cell Nucleus
• Adenomatous Polyposis Coli Protein (genetics)
• Animals
• Cell Nucleus (metabolism)
• Cell Transformation, Neoplastic (pathology)
• Colonic Neoplasms (metabolism, pathology)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors)
• Cyclooxygenase 2 (genetics, metabolism)
• Down-Regulation
• HCT116 Cells
• Humans
• Mice
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• Thionucleotides (pharmacology)
• beta Catenin (metabolism)