β-catenin signaling, the constitutive androstane receptor and their mutual interactions

Abstract

Aberrant signaling through β-catenin is an important determinant of tumorigenesis in rodents as well as in humans. In mice, xenobiotic activators of the constitutive androstane receptor (CAR), a chemo-sensing nuclear receptor, promote liver tumor growth by means of a non-genotoxic mechanism and, under certain conditions, select for hepatocellular tumors which contain activated β-catenin. In normal hepatocytes, interactions of β-catenin and CAR have been demonstrated with respect to the induction of proliferation and drug metabolism-related gene expression. The molecular details of these interactions are still not well understood. Recently it has been hypothesized that CAR might activate β-catenin signaling, thus providing a possible explanation for some of the observed phenomena. Nonetheless, many aspects of the molecular interplay of the two regulators have still not been elucidated. This review briefly summarizes our current knowledge about the interplay of CAR and β-catenin. By taking into account data and observations obtained with different mouse models and employing different experimental approaches, it is shown that published data also contain substantial evidence that xenobiotic activators of CAR do not activate, or do even inhibit signaling through the β-catenin pathway. The review highlights new aspects of possible ways of interaction between the two signaling cascades and will help to stimulate scientific discussion about the crosstalk of β-catenin signaling and the nuclear receptor CAR.

Keywords: Drug metabolism; Hepatocyte; Liver tumor promotion; Nuclear receptor; Wnt signaling.

Fig. 1

Schematic representation of the impact of CAR and/or β-catenin activation on the proliferation of hepatocytes and the formation of hepatocellular tumors. a CAR activation triggers a transient proliferative response in normal hepatocytes. Hepatocytes with activated β-catenin (due to gene mutations or transgene activation) do not proliferate under physiological conditions, but are stimulated to proliferate by the presence of CAR activators. b Under normal conditions, i.e. in the absence of a xenobiotic activator of CAR, pre-tumoral cells with activated β-catenin do not give rise to tumors, while other tumor precursor cell populations with activated MAPK signaling grow out to form hepatomas. Chronic treatment with a CAR activator inverts the situation and enables the selective outgrowth of tumors with activated β-catenin

Fig. 2

Scheme of interactions of CAR- and β-catenin-dependent signaling which may determine hepatocyte proliferation, tumor promotion and drug-metabolizing capacity. a Clear evidence is available for individual effects of CAR and β-catenin on the respective endpoints, as well as for a cooperation of the two pathways. There are still knowledge gaps with respect to the molecular details of the mutual interactions between the two players. b Phenobarbital as an indirect activator of CAR has been shown to exert CAR-independent effects on various molecular targets, including the β-catenin pathway. For more details, please refer to the main text