PT  - JOURNAL ARTICLE
AU  - Albert Braeuning
AU  - Ferdinand Kollotzek
AU  - Eva Zeller
AU  - Thomas Knorpp
AU  - Markus F. Templin
AU  - Michael Schwarz
TI  - Mouse hepatomas with Ha-ras and B-raf mutations differ in mitogen-activated protein kinase signaling and response to constitutive androstane receptor activation
AID  - 10.1124/dmd.118.083014
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.083014
4099  - http://dmd.aspetjournals.org/content/early/2018/08/16/dmd.118.083014.short
4100  - http://dmd.aspetjournals.org/content/early/2018/08/16/dmd.118.083014.full
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 CAR (constitutive androstane receptor), to analyze the response of chemically induced Ha-ras- and B-raf-mutated mouse liver adenoma to CAR activation in vivo. Both tumor sub-populations possess almost identical gene expression profiles. CAR target 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 phosphorylated 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.