Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands.
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| 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 beta-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 beta-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.
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| Authors | 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 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 32 Pg. 13481-6 (Aug 11 2009) ISSN: 1091-6490 [Electronic] United States |
| PMID | 19651607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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