Activation of the farnesoid X‐receptor suppresses cyclin D1 expression and decreases proliferation (1011.3)

Abstract

Bile acids have increasingly been recognized to play a modulatory role in cancer formation. We previously have shown that administering oral sodium taurocholate to APCmin/+ mice decreases cellular proliferation in intestinal crypts and markedly reduces adenoma formation . The current study validates that bile acids exhibit an anti‐proliferative effect through FXR‐mediated transcriptional activation of Small heterodimer partner (Shp) which, in turn, inhibits cyclin D1 expression. Human colon (HT‐29), breast (MCF7), hepatocellular (HepG2) carcinoma cells and nontransformed mouse hepatocytes (AML12) were incubated in the presence of a synthetic (GW4064) or native (chenodeoxycholic acid, CDCA) FXR agonist for 48 hours. All cell lines except HepG2 monolayers exhibited a significant decrease in cell proliferation at 24 h and 48 h. As expected, Shp mRNA and protein expression was significantly higher in treated cells (confirming activation of FXR), with a corresponding decrease in the expression of cyclin D1 mRNA and protein. Notably, cyclin D1 expression in HepG2 cells remained unchanged despite a significant increase in Shp expression. These data support the hypothesis that activation of FXR inhibits cell proliferation through down regulation of cyclin D1. The uncoupling of this effect in HepG2 cells might be a result of higher basal levels of FXR activity and Shp expression.