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A more recent version of this article appeared on May 1, 2004
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Submitted on December 16, 2003
Revised on February 19, 2004
Accepted on February 20, 2004
-catenin signaling pathway and increases colon cell cancer growth and invasiveness
1 Medical Service, Department of Veterans Affairs Medical Center, Long Beach, California, and the Department of Medicine, University of California, Irvine, CA 92717
* Corresponding author. E-mail address: rpai{at}uci.edu.
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. Since -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 (uPA), uPA receptor (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 siRNA 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.
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