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

2009; National Academy of Sciences; Volume: 106; Issue: 32 Linguagem: Inglês

10.1073/pnas.0902132106

1091-6490

Kaname Kawajiri, Yasuhito Kobayashi, Fumiaki Ohtake, Togo Ikuta, Yoshibumi Matsushima, Junsei Mimura, Sven Pettersson, Richard S. Pollenz, Toshiyuki Sakaki, Takatsugu Hirokawa, Tetsu Akiyama, Masafumi Kurosumi, Lorenz Poellinger, Shigeaki Kato, Yoshiaki Fujii‐Kuriyama,

Wnt/β-catenin signaling in development and cancer

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 β-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 β-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.