A nuclear receptor ligand down-regulates cytosolic phospholipase A2 expression to reduce bile acid-induced cyclooxygenase 2 activity in cholangiocytes: implications of anticarcinogenic action of farnesoid X receptor agonists.
Bile acids are considered to be involved in the development of biliary tract carcinoma, although the underlying mechanisms are yet to be established. The aims of this study were (1) to investigate the carcinogenic role of bile acids in the biliary system based on the arachidonate-prostanoid pathway and (2) to clarify the therapeutic role of a farnesoid X receptor (FXR) ligand that modifies bile acid metabolism. Immortalized mouse cholangiocytes were incubated with glycochenodeoxycholate (GCDC), taurocholate, taurochenodeoxycholate, taurodeoxycholate, and tauroursodeoxycholate. GCDC induced cyclooxygenase 2 (COX-2) expression (Western blotting, 1.7-fold; RT-PCR, 2.3-fold) and prostaglandin (PG) production (PGE2, 6.3-fold; PGF2alpha, 8.5-fold), whereas cytosolic phospholipase A2 (cPLA2) expression and activity were reduced. In contrast, no marked changes were induced by the other bile acids. When the same experiment was performed in the presence of a synthetic FXR ligand (GW4064), cPLA2 expression and activity were reduced, although COX-2 expression was unchanged. GW4064 also suppressed PG generation by 40%. In conclusion, the present findings suggest a carcinogenic potential of GCDC. A synthetic FXR ligand (GW4064) inhibited the induction of COX-2 activity (detected as PG production) by GCDC, suggesting its anticarcinogenic potential. This effect seemed to be due to down-regulation of cPLA2. FXR ligands may have therapeutic potential against biliary carcinogenesis, but a delivery system for these agents is still to be developed.
Komichi
Daisuke
D
Departments of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Tazuma
Susumu
S
Nishioka
Tomoji
T
Hyogo
Hideyuki
H
Chayama
Kazuaki
K
D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts; D001659:Biliary Tract / Q000166:cytology* / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D015536:Down-Regulation; D005786:Gene Expression Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011336:Probability; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D011451:Prostaglandin-Endoperoxide Synthases