Deoxycholic acid activates beta-catenin signaling pathway and increases colon cell cancer growth and invasiveness.
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.
Medical Service, Department of Veterans Affairs Medical Center, Long Beach, California, USA. rpai@uci.edu
Rama
R
Pai
Andrzej S
AS
Tarnawski
Teresa
T
Tran
D001681:Biological Assay; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; C524898:PLAUR protein, human; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D015534:Trans-Activators; D051176:beta Catenin; D003840:Deoxycholic Acid; D019938:Cyclin D1; D014443:Tyrosine; D014568:Urokinase-Type Plasminogen Activator