INVOLVEMENT OF MEMBRANE-TYPE BILE ACID RECEPTOR M-BAR/TGR5 IN BILE ACID-INDUCED ACTIVATION OF EPIDERMAL GROWTH FACTOR RECEPTOR AND MITOGEN-ACTIVATED PROTEIN KINASES IN GASTRIC CARCINOMA CELLS.

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Bile acids, which have been implicated in carcinogenesis of the gastrointestinal tract, share properties of tumor promoters in that both affect cell signal-transduction pathways responsible for cell proliferation. The results of several studies suggest that mitogen-activated protein kinase activation is involved in the cellular effects of bile acids. In the present study, we demonstrate that treatment of AGS human gastric carcinoma cells with bile acids results in activation of epidermal growth factor receptor (EGFR)-extracellular signal regulated kinase (ERK)1/2, which is also important for regulating cellular growth. Phosphoactivation of EGFR following treatment of cells with deoxycholate (DC) is ligand-dependent, since treatment of cells with heparin-binding EGF-like growth factor (HB-EGF) antisera or CM197 (a selective inhibitor of HB-EGF) markedly inhibited. Membrane-type bile acid receptor (M-BAR) BG37/TGR5 is a recently identified GPCR (G-protein-coupled receptor) for bile acids. Introduction of siRNAs that target M-BAR mRNA for degradation results in potent suppression of DC-induced phosphorylation of EGFR on tyrosine, as well as ERK1/2 activation, in AGS cells. Furthermore, pretreatment of cells with the metalloprotease inhibitor BiPS resulted in potent inhibition of DC-induced EGFR activation in AGS cells. Finally, introduction of siRNAs targeting ADAM17 transcripts resulted in suppression of DC-induced activation of EGFR and ERK1/2. These results lead us to conclude that bile acids transactivate EGFR through M-BAR-and ADAM/HB-EGF-dependent mechanisms in AGS cells. M-BAR, which may be involved in gastric carcinogenesis, could potentially serve as a target for cancer prevention.