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PMID: 15004225 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S.

Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness.

Molecular biology of the cell ·Vol. 15 ·No. 5 ·2004-05-00 ·Pages 2156-63

Pai R, Tarnawski AS, Tran T

Abstract

Colorectal cancer is often lethal when invasion and/or metastasis occur. Tumor progression to the metastatic phenotype is mainly dependent on tumor cell invasiveness. Secondary bile acids, particularly deoxycholic acid (DCA), are implicated in promoting colon cancer growth and progression. Whether DCA modulates beta-catenin and promotes colon cancer cell growth and invasiveness remains unknown. Because beta-catenin and its target genes urokinase-type plasminogen activator receptor (uPAR) and cyclin D1 are overexpressed in colon cancers, and are linked to cancer growth, invasion, and metastasis, we investigated whether DCA activates beta-catenin signaling and promotes colon cancer cell growth and invasiveness. Our results show that low concentrations of DCA (5 and 50 microM) significantly increase tyrosine phosphorylation of beta-catenin, induce urokinase-type plasminogen activator, uPAR, and cyclin D1 expression and enhance colon cancer cell proliferation and invasiveness. These events are associated with a substantial loss of E-cadherin binding to beta-catenin. Inhibition of beta-catenin with small interfering RNA significantly reduced DCA-induced uPAR and cyclin D1 expression. Blocking uPAR with a neutralizing antibody significantly suppressed DCA-induced colon cancer cell proliferation and invasiveness. These findings provide evidence for a novel mechanism underlying the oncogenic effects of secondary bile acids.

MeSH Terms
Biological Assay Cadherins/genetics,metabolism Cell Line Colonic Neoplasms/metabolism,pathology Cyclin D1/genetics,metabolism Cytoskeletal Proteins/metabolism Deoxycholic Acid/metabolism,pharmacology Gene Expression Regulation Humans Neoplasm Invasiveness Phosphorylation/drug effects RNA, Small Interfering/genetics Receptors, Cell Surface/genetics,metabolism Receptors, Urokinase Plasminogen Activator Signal Transduction Trans-Activators/metabolism Tyrosine/drug effects Urokinase-Type Plasminogen Activator/genetics,metabolism beta Catenin
Chemicals
CTNNB1 protein, human Cadherins Cytoskeletal Proteins PLAUR protein, human RNA, Small Interfering Receptors, Cell Surface Receptors, Urokinase Plasminogen Activator Trans-Activators beta Catenin Deoxycholic Acid Cyclin D1 Tyrosine Urokinase-Type Plasminogen Activator
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Pai Rama
Medical Service, Department of Veterans Affairs Medical Center, Long Beach, California, USA. rpai@uci.edu
Tarnawski Andrzej S
Tran Teresa
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Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.e03-12-0894
Email
rpai@uci.edu
Published
2004-05-00
Epub
2004-00-05
Pages
2156-63
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC404012
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.e03-12-0894 PMC Full Text View journal details
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