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

Kristoffer W Brudvik,Borghild Roald,Jan E Paulsen,Kjetil Taskén,Einar M Aandahl

doi:10.1186/1476-4598-10-149

Kristoffer W Brudvik, Borghild Roald + Show 3 more

Open Access

https://doi.org/10.1186/1476-4598-10-149

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Abstract

BackgroundThe 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 E2 (PGE2) - PI-3 kinase pathways. Recent reports show that PGE2-induced phosphorylation of β-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE2 on β-catenin homeostasis.FindingsTreatment of ApcMin/+ 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 PGE2-induced β-catenin phosphorylation and c-Myc upregulation.ConclusionBased on our findings we suggest that PGE2 act through PKA to promote β-catenin nuclear translocation and tumor development in ApcMin/+ mice in vivo, indicating that the direct regulatory effect of PKA on β-catenin nuclear translocation is operative in intestinal cancer.

Highlights

The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of b-catenin and limiting its nuclear translocation, which is thought to play a gatekeeping role in colorectal cancer
The APC protein forms a destruction complex with Axin, glycogen synthase kinase 3b (GSK3b) and casein kinase 1 (CK1) which phosphorylates b-catenin at multiple sites [2], and targets b-catenin for ubiquitination and to degradation
Studies have shown that COX inhibition by non-steroidal anti-inflammatory drugs (NSAIDS) or aspirin reduces the risk of CRC and may be beneficial in large population groups at risk [9]

Summary

Introduction

The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of b-catenin and limiting its nuclear translocation, which is thought to play a gatekeeping role in colorectal cancer. We show that treatment of ApcMin/+ mice with a PKA antagonist, Rp-8-Br-cAMPS, reduces tumor load, b-catenin levels and nuclear translocation as well as expression of b-catenin target genes in ApcMin/+ mice in vivo.

Results

Conclusion