title: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership and Biotechnology Centre, University of Oslo, Oslo, Norway.
authors.forename: Kristoffer W
authors.initials: KW
authors.lastname: Brudvik
authors.forename: Jan E
authors.initials: JE
authors.lastname: Paulsen
authors.forename: Einar M
authors.initials: EM
authors.lastname: Aandahl
authors.forename: Borghild
authors.initials: B
authors.lastname: Roald
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C105593:8-bromoadenosine-3',5'-cyclic monophosphorothioate; D025601:Adenomatous Polyposis Coli Protein; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D013873:Thionucleotides; D051176:beta Catenin; D015124:8-Bromo Cyclic Adenosine Monophosphate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D017868:Cyclic AMP-Dependent Protein Kinases