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Carcinogenesis, Vol. 22, No. 1, 35-41, January 2001
© 2001 Oxford University Press

CANCER BIOLOGY

Activation and role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis

Dianhua Qiao, Elias D. Stratagouleas and Jesse D. Martinez1

Arizona Cancer Center, Department of Radiation Oncology, University of Arizona, 1501 North Campbell Avenue, Tucson, AZ 85724, USA

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.


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