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Vol. 12, Issue 9, 2629-2645, September 2001

Deoxycholic Acid (DCA) Causes Ligand-independent Activation of Epidermal Growth Factor Receptor (EGFR) and FAS Receptor in Primary Hepatocytes: Inhibition of EGFR/Mitogen-activated Protein Kinase-Signaling Module Enhances DCA-induced Apoptosis

Liang Qiao,* Elaine Studer,dagger Kevin Leach,* Robert McKinstry,* Seema Gupta,dagger Roy Decker,Dagger Rakesh Kukreja,§ Kristoffer Valerie,* Prakash Nagarkatti,dagger Wafik El Deiry,|| Jeffrey Molkentin, Rupert Schmidt-Ullrich,* Paul B. Fisher, Steven Grant,Dagger Philip B. Hylemon, and Paul Dent*dagger @

 *Departments of Radiation Oncology,  Dagger Hematology/Oncology,  §Cardiology, and  dagger Microbiology and Immunology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298;  Department of Pediatrics, University of Cincinnati, Children's Hospital of Cincinnati, Cincinnati, Ohio 45229;  ||Howard Hughes Medical Institute, Department of Medicine, Cancer Center and Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; and  #Department of Urology and Pathology, Columbia University College of Physicians and Surgeons, New York, New York 10032

Previous studies have argued that enhanced activity of the epidermal growth factor receptor (EGFR) and the mitogen-activated protein kinase (MAPK) pathway can promote tumor cell survival in response to cytotoxic insults. In this study, we examined the impact of MAPK signaling on the survival of primary hepatocytes exposed to low concentrations of deoxycholic acid (DCA, 50 µM). Treatment of hepatocytes with DCA caused MAPK activation, which was dependent upon ligand independent activation of EGFR, and downstream signaling through Ras and PI3 kinase. Neither inhibition of MAPK signaling alone by MEK1/2 inhibitors, nor exposure to DCA alone, enhanced basal hepatocyte apoptosis, whereas inhibition of DCA-induced MAPK activation caused ~25% apoptosis within 6 h. Similar data were also obtained when either dominant negative EGFR-CD533 or dominant negative Ras N17 were used to block MAPK activation. DCA-induced apoptosis correlated with sequential cleavage of procaspase 8, BID, procaspase 9, and procaspase 3. Inhibition of MAPK potentiated bile acid-induced apoptosis in hepatocytes with mutant FAS-ligand, but did not enhance in hepatocytes that were null for FAS receptor expression. These data argues that DCA is causing ligand independent activation of the FAS receptor to stimulate an apoptotic response, which is counteracted by enhanced ligand-independent EGFR/MAPK signaling. In agreement with FAS-mediated cell killing, inhibition of caspase function with the use of dominant negative Fas-associated protein with death domain, a caspase 8 inhibitor (Ile-Glu-Thr-Asp-p-nitroanilide [IETD]) or dominant negative procaspase 8 blocked the potentiation of bile acid-induced apoptosis. Inhibition of bile acid-induced MAPK signaling enhanced the cleavage of BID and release of cytochrome c from mitochondria, which were all blocked by IETD. Despite activation of caspase 8, expression of dominant negative procaspase 9 blocked procaspase 3 cleavage and the potentiation of DCA-induced apoptosis. Treatment of hepatocytes with DCA transiently increased expression of the caspase 8 inhibitor proteins c-FLIP-S and c-FLIP-L that were reduced by inhibition of MAPK or PI3 kinase. Constitutive overexpression of c-FLIP-s abolished the potentiation of bile acid-induced apoptosis. Collectively, our data argue that loss of DCA-induced EGFR/Ras/MAPK pathway function potentiates DCA-stimulated FAS-induced hepatocyte cell death via a reduction in the expression of c-FLIP isoforms.

@ Corresponding author. E-mail address: pdent{at}hsc.vcu.edu.

Molecular Biology of the Cell
Vol. 12, 2629-2645, September 2001
Copyright © 2001 by The American Society for Cell Biology


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