Activation and role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis.
The bile acid deoxycholic acid (DCA) is a known tumor promoter and it has been suggested that DCA-induced apoptosis plays an important role in colon tumor development. In this study we have characterized the capacity of DCA to stimulate mitogen-activated protein kinase (MAPK) activity and examined the effect that MAPK activity had on DCA-induced apoptosis. Analysis of MAPK activity in DCA-treated HCT116 cells using phosphorylation-specific antibodies and in vitro kinase assays indicated that both the extracellular signal-regulated kinase (ERK) and p38 MAPK (p38), but not the c-Jun N-terminal kinase (JNK), were activated. Using pharmacological inhibitors we determined that only ERK could influence DCA cytotoxicity and that elevated ERK activity could suppress DCA-induced apoptosis. This observation was confirmed genetically. Suppressing ERK activity by overexpressing a dominant negative form of the ERK MAP kinase resulted in increased sensitivity to DCA-induced apoptosis whereas elevated ERK activity artificially produced by overexpression of the wild-type ERK kinase blunted DCA-induced apoptosis. Taken together, our results suggest that DCA can stimulate pro-apoptotic and anti-apoptotic signaling pathways and that sensitivity to DCA-induced apoptosis can be modulated by the ERK MAP kinase.
Qiao
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D
Arizona Cancer Center, Department of Radiation Oncology, University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724, USA.
Stratagouleas
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ED
Martinez
J D
JD
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D003840:Deoxycholic Acid / Q000633:toxicity*; D015536:Down-Regulation / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D005419:Flavonoids; D003840:Deoxycholic Acid; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one