RT Journal Article
SR Electronic
T1 Mouse Hepatomas with <em>Ha-ras</em> and <em>B-raf</em> Mutations Differ in Mitogen-Activated Protein Kinase Signaling and Response to Constitutive Androstane Receptor Activation
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1462
OP 1465
DO 10.1124/dmd.118.083014
VO 46
IS 11
A1 Albert Braeuning
A1 Ferdinand Kollotzek
A1 Eva Zeller
A1 Thomas Knorpp
A1 Markus F. Templin
A1 Michael Schwarz
YR 2018
UL http://dmd.aspetjournals.org/content/46/11/1462.abstract
AB Nuclear receptors mediate the hepatic induction of drug-metabolizing enzymes by xenobiotics. Not much is known about enzyme induction in liver tumors. Here, we treated tumor-bearing mice with phenobarbital, an activator of the constitutive androstane receptor (CAR), to analyze the response of chemically induced Ha-ras- and B-raf-mutated mouse liver adenoma to CAR activation in vivo. Both tumor subpopulations possess almost identical gene expression profiles. CAR target gene induction in the tumors was studied at the mRNA and protein levels, and a reverse-phase protein microarray approach was chosen to characterize important signaling cascades. CAR target gene induction was pronounced in B-raf-mutated but not in Ha-ras-mutated tumors. Phosphoproteomic profiling revealed that phosphorylation-activated extracellular signal-regulated kinase (ERK) 1/2 was more abundant in Ha-ras-mutated than in B-raf-mutated tumors. ERK activation in tumor tissue was negatively correlated with CAR target induction. ERK activation is known to inhibit CAR-dependent transcription. In summary, profound differences exist between the two closely related tumor subpopulations with respect to the activation of mitogenic signaling cascades, and these dissimilarities might explain the differences in xenobiotic induction of CAR target genes.