Bile acid-induced proliferation of a human colon cancer cell line is mediated by transactivation of epidermal growth factor receptors.
Although epidemiological studies indicate an association between elevations in fecal bile acids and the development of colorectal cancer, the cellular mechanism for the proliferative actions of bile acids is not clear. Studies from other laboratories indicate a paradoxical pro-apoptotic action of bile acids on cell culture lines. Our previous studies indicate that cholinergic agonist-induced proliferation of colon cancer cells that express M3 muscarinic receptors (M3R) is mediated by transactivation of the epidermal growth factor receptor (EGFR) and that bile acids stimulate proliferation of colon cancer cells that express M3R. In the present study, we investigated the effects of bile acids on cell signaling and proliferation of a human colon cancer cell line (H508 cells) that abundantly expresses M3R and EGFR. Treatment with taurine and glycine conjugates of lithocholic and deoxycholic acids stimulated reversible activation of the p44/42 MAP kinase signaling cascade and proliferation of H508 cells. Bile acids did not stimulate proliferation of SNU-C4 colon cancer cells that express EGFR but not muscarinic receptors. Atropine, a muscarinic receptor inverse agonist, blocked bile acid-induced H508 cell proliferation. At concentrations that stimulate cell proliferation, conjugated bile acids did not activate caspase-3, a key mediator of apoptosis. Conjugated bile acids stimulated phosphorylation of EGFR Tyr992, thereby implicating EGFR transactivation in the cellular mechanism underlying their proliferative actions. This was confirmed by observing that inhibitors of EGFR activation and antibodies to the ligand-binding domain of EGFR blocked both the signaling and proliferative actions of bile acids. Collectively, these results suggest that in this colon cancer cell line, bile acid-induced colon cancer cell proliferation is M3R-dependent and is mediated by transactivation of EGFR.
Cheng
Kunrong
K
Division of Gastroenterology and Hepatology, VA Maryland Health Care System and Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, 22 S. Green Street, N3W62 Baltimore, MD 21201, USA.
Raufman
Jean-Pierre
JP
D000109:Acetylcholine / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation
D001647:Bile Acids and Salts; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000109:Acetylcholine