title: Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ 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 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.
authors: Research Institute for Clinical Oncology and Hospital, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan. kawajiri@cancer-c.pref.saitama.jp
authors: Kaname
authors: K
authors: Kawajiri
authors: Yasuhito
authors: Y
authors: Kobayashi
authors: Fumiaki
authors: F
authors: Ohtake
authors: Togo
authors: T
authors: Ikuta
authors: Yoshibumi
authors: Y
authors: Matsushima
authors: Junsei
authors: J
authors: Mimura
authors: Sven
authors: S
authors: Pettersson
authors: Richard S
authors: RS
authors: Pollenz
authors: Toshiyuki
authors: T
authors: Sakaki
authors: Takatsugu
authors: T
authors: Hirokawa
authors: Tetsu
authors: T
authors: Akiyama
authors: Masafumi
authors: M
authors: Kurosumi
authors: Lorenz
authors: L
authors: Poellinger
authors: Shigeaki
authors: S
authors: Kato
authors: Yoshiaki
authors: Y
authors: Fujii-Kuriyama
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D002430:Cecal Neoplasms / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination; D051176:beta Catenin / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex