Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in Apc ^{Min /+} mice with natural ligands

Abstract

Intestinal cancer is one of the most common human cancers. Aberrant activation of the canonical Wnt signaling cascade, for example, caused by adenomatous polyposis coli (APC) gene mutations, leads to increased stabilization and accumulation of ␤-catenin, resulting in initiation of intestinal carcinogenesis. The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels both as a ligand-activated transcription factor and as a ligand-dependent E3 ubiquitin ligase. Here, we show that the AhR E3 ubiquitin ligase has a role in suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent ␤-catenin degradation pathway that is independent of and parallel to the APC system. This function of AhR is activated by both xenobiotics and natural AhR ligands, such as indole derivatives that are converted from dietary tryptophan and glucosinolates by intestinal microbes, and suppresses intestinal tumor development in Apc Min/؉ mice. These findings suggest that chemoprevention with naturally-occurring and chemically-designed AhR ligands can be used to successfully prevent intestinal cancers.cecal cancer ͉ ubiquitin ligase ͉ ␤-catenin ͉ tumor chemoprevention

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

“…12,13 In addition to its transcriptional roles, it mediates degradation of proteins through the ubiquitin ligase complex. 14,15 Several endogenous chemicals, including IS, bind to and activate the AHR. 12,16 Therefore, we hypothesized that IS accumulation in CKD patients induces TF through an AHR pathway, thus potentiating thrombosis.…”

Characterization of Natural Aryl Hydrocarbon Receptor Agonists from Cassia Seed and Rosemary

“…In contrast, compounds 12-14 induced cell death at 10 3 μM ( Figure 5). Moreover, nepitrin (15) and homoplantagenin (16), which are flavone glucosides, showed marked AhR-binding activity at concentrations ranging from 10-10 3 μM lower than those required for binding by indole 3-acetic acid (IAA), a typical natural AhR ligand [8].…”

“…1-10). , were purified by preparative TLC to afford eight compounds: chryso-obtusin (1), obtusifolin (2), obtusin (3), aurantioobtusin (4), obtusin 2-O-glucoside (5), aurantio-obtusin 6-O-glucoside (6), nor-rubrofusarin 6-Oglucoside (7), and 6-hydroxymusizin 8-O-glucoside (8). Among these isolates, aurantio-obtusin (4) elicited marked AhR activation, followed by obtusifolin (2) and obtusin (3).…”

“…The AhR has been identified as a target of several signaling pathways that cross-talk with its own regulatory pathway, such as proteasomal degradation, redox-sensitive transcription factors, and mitogen-activated protein kinases (MAPKs) [7,8]. Several studies have also found that the AhR plays an important role in immune system function [9][10][11][12].…”

Establishment of a stable aryl hydrocarbon receptor-responsive HepG2 cell line

“…AHR functions as a ligand-dependent E3 ubiquitin ligase of certain nuclear receptors (Ohtake et al 2007). Kawajiri et al (2009) reported that AHR played a critical role in the suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent mechanism of proteasomal b-catenin degradation and the natural AHR ligands of indole derivatives such as indole-3-carbinol and 3,3-diindolylmethane suppressed intestinal carcinogenesis in an AHR-dependent manner. More recently, there have been some reports that AHR plays an important role in the modulation of the intestinal immune system (Hooper 2011).…”