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Vol. 15, Issue 5, 2156-2163, May 2004

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Deoxycholic Acid Activates -Catenin Signaling Pathway and Increases Colon Cell Cancer Growth and Invasiveness

Medical Service, Department of Veterans Affairs Medical Center, Long Beach, California; and the Department of Medicine, University of California, Irvine, California 92717

Submitted December 16, 2003; Revised February 19, 2004; Accepted February 20, 2004
Monitoring Editor: Carl-Henrik Heldin

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 -catenin and promotes colon cancer cell growth and invasiveness remains unknown. Because -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 -catenin signaling and promotes colon cancer cell growth and invasiveness. Our results show that low concentrations of DCA (5 and 50 µM) significantly increase tyrosine phosphorylation of -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 -catenin. Inhibition of -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.

Abbreviations used: APC, adenomatous polyposis coli; DCA, deoxycholic acid; GSK, glycogen synthase kinase; TCF, T cell factor; uPA, urokinase-type plasminogen activator; uPAR, urokinase-type plasminogen activator receptor.

^* Corresponding author. E-mail address: rpai{at}uci.edu.

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