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

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...

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Autores principales: Brudvik, Kristoffer W, Paulsen, Jan E, Aandahl, Einar M, Roald, Borghild, Taskén, Kjetil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278393/
https://www.ncbi.nlm.nih.gov/pubmed/22168384
http://dx.doi.org/10.1186/1476-4598-10-149
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author Brudvik, Kristoffer W
Paulsen, Jan E
Aandahl, Einar M
Roald, Borghild
Taskén, Kjetil
author_facet Brudvik, Kristoffer W
Paulsen, Jan E
Aandahl, Einar M
Roald, Borghild
Taskén, Kjetil
author_sort Brudvik, Kristoffer W
collection PubMed
description 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.
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spelling pubmed-32783932012-02-14 Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+ )mice Brudvik, Kristoffer W Paulsen, Jan E Aandahl, Einar M Roald, Borghild Taskén, Kjetil Mol Cancer Short Communication 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. BioMed Central 2011-12-15 /pmc/articles/PMC3278393/ /pubmed/22168384 http://dx.doi.org/10.1186/1476-4598-10-149 Text en Copyright ©2011 Brudvik et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Short Communication
Brudvik, Kristoffer W
Paulsen, Jan E
Aandahl, Einar M
Roald, Borghild
Taskén, Kjetil
Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+ )mice
title Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+ )mice
title_full Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+ )mice
title_fullStr Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+ )mice
title_full_unstemmed Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+ )mice
title_short Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+ )mice
title_sort protein kinase a antagonist inhibits β-catenin nuclear translocation, c-myc and cox-2 expression and tumor promotion in apc(min/+ )mice
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278393/
https://www.ncbi.nlm.nih.gov/pubmed/22168384
http://dx.doi.org/10.1186/1476-4598-10-149
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