The Bile Acid Nuclear Receptor FXR and the Bile Acid Binding Protein IBABP Are Differently Expressed in Colon Cancer

Abstract

Bile acids have been implicated in the development of colorectal cancers. We investigated the expression of the transcription factor regulated by bile acids, farnesoid X receptor (FXR), as well as other components of this pathway in human colorectal tumors and cell lines. The most significant changes were a decrease in FXR mRNA levels in adenomas (5-fold average) and carcinomas (10 fold average) and an increase in peroxisome proliferator activated receptor-gamma (2-fold average). FXR was not expressed in undifferentiated colon adenocarcinoma SW480 cells and metastasis derived SW620 cells. In Caco-2 and HT-29 cells, the level of FXR expression increased with the degree of differentiation. Intestinal bile acid binding protein was activated by chenodeoxycholic acid and the synthetic FXR agonist GW4064 in Caco-2 and HT-29 but not in SW cells unless FXR was transfected. The down-regulation of the nuclear receptor FXR in colon cancer might be of clinical and pharmacological importance.

Biotransformation of Lithocholic Acid by Rat Hepatic Microsomes: Metabolite Analysis by Liquid Chromatography/Mass Spectrometry

“…Lithocholic acid concentrations of 5 to 10 M have been reported in the liver of cholestatic patients and in rat models of biliary cholestasis (Jezequel et al, 1994;Fischer et al, 1996;Erlinger, 1997;Setchell et al, 1997;Hofmann, 2002;Berta et al, 2003;Rost et al, 2003;De Gottardi et al, 2004). A lithocholic acid concentration of 100 M was found to be saturating for hepatic microsomal MDCA formation in the present study.…”

“…In comparison, the major bile acids in human liver, which are cholic acid and CDCA, and the major bile acids in rat liver, which are cholic acid and muricholic acid, are present at concentrations that are 5 to 10 times greater (Setchell et al, 1997). Hepatic lithocholic acid concentrations are elevated in patients with cholestatic liver disease (Jezequel et al, 1994;Fischer et al, 1996;Erlinger, 1997;Hofmann, 2002;Berta et al, 2003;De Gottardi et al, 2004) and in rat models of biliary cholestasis (Setchell et al, 1997;Rost et al, 2003). The accumulation of lithocholic acid and other hydrophobic bile acids in liver has been implicated as a major factor contributing to liver injury in cholestasis because of the inherent cytotoxicity of this hydrophobic bile acid.…”

Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients

“…Indeed, FXR mRNA levels decrease in colon adenomas and even more in colon carcinomas, and become undetectable in undifferentiated colon adenocarcinoma SW480 cells and in metastasis-derived SW620 cells. On the other hand, FXR gene expression increases with the degree of differentiation in the Caco-2 and HT-29 cell lines [26]. Thus, lesser expression of FXR seems to be associated with a more undifferentiated phenotype in breast and colon carcinomas.…”

Intestinal bile acid physiology and pathophysiology

“…In addition, DCA may increase tumor invasiveness by activation of beta-catenin signaling [81] . An interesting observation is that FXR expression is diminished in colon cancer [82] . Under these circumstances, FXR-mediated mechanisms involved in the prevention of BA accumulation in these cells could be expected to be completely or partly inactive, thus exacerbating BA-induced effects.…”