Aryl Hydrocarbon Receptor Suppresses Cecal Carcinogenesis

Abstract

The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels as both a ligand-activated transcription factor and a ligand-dependent E3 ubiquitin ligase. We showed that the AhR E3 ubiquitin ligase has a role in the suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent β-catenin degradation pathway. 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 which suppresses intestinal tumor development in Apc Min/+ mice. To elucidate whether the tumors develop autonomously in AhR −/− mice as a result of impaired β-catenin degradation or in association with accelerated inflammation, we performed two kinds of experiments using germ-free (GF) AhR −/− mice or compound mutant mice lacking genes for AhR and adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which play an essential role in caspase-1 activation in inflammasomes. Both GF AhR −/− and AhR −/− •ASC −/− mice showed considerably reduced tumor development compared with that in AhR −/− mice, albeit in a “cancer-prone” state with aberrant β-catenin accumulation. These results revealed an important role of the bacteria-triggered or ASC-mediated inflammation signaling pathway in mouse intestinal tumorigenesis. Furthermore, they also suggest a possible chemical therapeutic intervention that involves AhR ligands and inhibitors of the inflammation pathway.