Abstract B70: Inhibition of nuclear bile acid receptor FXR as a target in prevention of esophageal adenocarcinoma

Abstract

Abstract Incidence of esophageal adenocarcinoma is increasing in the United States and other Western countries. Frequent gastroesophageal reflux or gastroesophageal reflux disease, resulting in Barrett esophagus, may be responsible for the increase. The main function of bile acid is to facilitate the formation of micelles for promotion of the processing and absorption of dietary fat. As surfactants or detergents, bile acids are potentially toxic to the cells, so their concentrations in the small intestine are tightly regulated. However, patients with frequent gastroesophageal reflux will have reflux damage caused by acid and bile acid-containing juice in the distal esophagus, with the result that normal squamous cells around the gastroesophageal junction will change to a new cell phenotype (incomplete intestinal metaplasia), because this type of cell is more resistant to acid and bile-caused injuries; therefore, Barrett esophagus is formed. This study aimed to determine the tumor-promoting effects of bile acid on esophageal cancer cells and the underlying molecular mechanisms. The data showed that different bile acids (i.e., chenodeoxycholic acid, deoxycholic acid, and lithocholic acid) induced COX-2 but inhibited RAR-β2 expression through farnesoid X receptor (FXR) expression in esophageal cancer cell lines. FXR is a nuclear receptor for bile acids functioning as a signaling molecule in the liver and the intestines and frequent gastroesophageal reflux induces FXR expression in esophageal cells. Indeed, the ex vivo data demonstrated that FXR was highly expressed in esophageal adenocarcinoma (81%) tissues and was associated with reduced RAR-β2 expression. Knockdown of FXR expression using FXR shRNA antagonized the effects of bile acid in gene expression and suppressed tumor cell viability in vitro and in nude mouse xenografts. Moreover, guggulsterone, a FXR inhibitor, was able to reduce the viability of esophageal cancer cells in time- and dose-dependent manner in vitro. Apoptosis induced by guggulsterone was through activation of caspase 8, 9, and 3. In conclusion, suppression of FXR expression using FXR shRNA or its inhibitor guggulsterone was able to suppress tumor cell growth in vitro and in vivo and induce apoptosis in vitro. This study demonstrated that inhibition of FXR could be further evaluated as a target in prevention of esophageal adenocarcinoma. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B70.