Regulation of expression of drug-metabolizing enzymes by oncogenic signaling pathways in liver tumors: a review

Abstract

Mutations in genes encoding key players in oncogenic signaling pathways trigger specific downstream gene expression profiles in the respective tumor cell populations. While regulation of genes related to cell growth, survival, and death has been extensively studied, much less is known on the regulation of drug-metabolizing enzymes (DMEs) by oncogenic signaling. Here, a comprehensive review of the available literature is presented summarizing the impact of the most relevant genetic alterations in human and rodent liver tumors on the expression of DMEs with a focus on phases I and II of xenobiotic metabolism. Comparably few data are available with respect to DME regulation by p53-dependent signaling, telomerase expression or altered chromatin remodeling. By contrast, DME regulation by constitutive activation of oncogenic signaling via the RAS/RAF/mitogen-activated protein kinase (MAPK) cascade or via the canonical WNT/β-catenin signaling pathway has been analyzed in greater depth, demonstrating mostly positive-regulatory effects of WNT/β-catenin signaling and negative-regulatory effects of MAPK signaling. Mechanistic studies have revealed molecular interactions between oncogenic signaling and nuclear xeno-sensing receptors which underlie the observed alterations in DME expression in liver tumors. Observations of altered DME expression and inducibility in liver tumors with a specific gene expression profile may impact pharmacological treatment options.

Keywords: Cytochrome P450; Gene mutation; Hepatocytes; RAS/MAPK signaling; WNT/β-catenin signaling; Xenobiotic metabolism.

Graphical abstract

Figure 1

Overview of the phases and important enzymes and transporters of xenobiotic metabolism in hepatocytes. Functionalization in phase I is followed by conjugation to endogenous substrates in phase II and excretion in phase III of the biotransformation process. Abbreviations: COX, cyclooxygenase; CYP, cytochrome P450; EH, epoxide hydrolase; GST, glutathione-S-transferase; MAO, monoamine oxidase; MDR, multi-drug resistance protein; MRP, multi-drug resistance-related protein; NAT, N-acetyltransfease; NQO, NAD(P)H-quinone oxidoreductase; OAT, organic anion transporter; OATP, organic anion-transporting peptide; OCT, organic cation transporter; UGT, UDP-glucuronosyl-transferase.

Figure 2

DME characteristics of chemically induced mouse liver tumors with activating mutations in the Ctnnb1, Hras, or Braf proto-oncogenes. Spontaneous tumors or tumors induced by application of the genotoxic tumor initiator N-nitrosodiethylamine (DEN) mostly leads to tumors with activated MAPK signaling due to mutations in Hras or Braf. By contrast, chronic treatment with the tumor promoter phenobarbital (PB) or similarly acting compounds leads to the outgrowth of liver tumors with activated β-catenin due to activating Ctnnb1 mutations. Tumors with Hras and Braf mutations generally express low basal levels of DMEs (esp. CYPs and GSTs). In contrast to Hras-mutated tumors which are refractory to DME induction by constitutive androstane receptor (CAR) agonists, mouse liver tumors with Braf mutations respond to CAR activation with CYP and GST induction. Hepatomas with activated β-catenin display high constitutive expression of DMEs. For more details, please refer to the main text.

Figure 3

Mechanistic aspects of DME regulation in mouse liver tumors with mutations in either the Ctnnb1, Hras, or Braf oncogene. Signaling through β-catenin affects DME gene expression by different mechanisms involving β-catenin/TCF-dependent promoter activation and various ways of cooperation with nuclear xeno-sensing receptors, e.g., AHR and CAR. Moreover, synthesis of the CYP prosthetic group heme is augmented by β-catenin signaling in hepatocytes. Tumors with mutationally activated HA-RAS harbor high levels of phosphorylated, active extracellular signal-regulated kinase (ERK) 1/2. Phosphorylated ERK retains the constitutive androstane receptor (CAR) in the cytosol to inhibit DME induction by CAR agonists. This phenomenon is not observed in tumors with mutationally activated B-RAF, where ERK phosphorylation is much less pronounced. Antagonistic action of the DME-inhibiting mitogen-activated protein kinase (MAPK) pathway and the DME-inducing β-catenin pathway have been described, for example via the induction of dual-specificity phosphatases (DUSP) by the β-catenin pathway. For more details, please refer to the main text.