title: Nuclear bile acid receptor FXR protects against intestinal tumorigenesis.
abstract: Bile acids have been considered intestinal tumor promoters, and because they are natural ligands for the nuclear receptor FXR, we examined the role of FXR in intestinal tumorigenesis. Using gain- and loss-of-function studies, we found that FXR suppresses intestinal tumorigenesis in vivo. Loss of FXR in the ApcMin/+ and in the chronic colitis mouse models of intestinal tumorigenesis resulted in early mortality and increased tumor progression via promotion of Wnt signaling by infiltrating neutrophils and macrophages and tumor necrosis factor alpha production. Treatment with the bile acid binding resin cholestyramine did not modify the intestinal tumor susceptibility of FXR-/- mice, indicating that loss of FXR and not merely elevated bile acid concentrations increases susceptibility to tumorigenesis. Activation of FXR induced a proapoptotic program in the differentiated normal colonic epithelium as well as transformed colonocytes. Our data suggest that it is unlikely that the tumor-promoting activity of bile acids occurs as a function of their ability to activate FXR. However, FXR activity is relevant to the pathogenesis of intestinal cancer. When FXR is absent in the intestine, there is a promotion of Wnt signaling with expansion of the basal proliferative compartment, and a concomitant reduction in the apical differentiated apoptosis-competent compartment. When FXR is activated in the intestine and in colon cancer cells, there is an induction of apoptosis and removal of genetically altered cells, which may otherwise progress to complete transformation. Thus, from a therapeutic standpoint, strategies aimed at reactivating FXR expression in colon tumors might be useful in treatment of colon cancer.
authors.affiliation: Laboratory of Lipid Metabolism and Cancer, Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa MariaImbaro, Chieti and Clinica Medica A. Murri, University of Bari, Bari, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Modica
authors.forename: Stefania
authors.initials: S
authors.lastname: Murzilli
authors.forename: Lorena
authors.initials: L
authors.lastname: Salvatore
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Schmidt
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D007178:Inbreeding; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated