Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands.
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.
Kawajiri
Kaname
K
Research Institute for Clinical Oncology and Hospital, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan. kawajiri@cancer-c.pref.saitama.jp
Kobayashi
Yasuhito
Y
Ohtake
Fumiaki
F
Ikuta
Togo
T
Matsushima
Yoshibumi
Y
Mimura
Junsei
J
Pettersson
Sven
S
Pollenz
Richard S
RS
Sakaki
Toshiyuki
T
Hirokawa
Takatsugu
T
Akiyama
Tetsu
T
Kurosumi
Masafumi
M
Poellinger
Lorenz
L
Kato
Shigeaki
S
Fujii-Kuriyama
Yoshiaki
Y
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
D025601:Adenomatous Polyposis Coli Protein; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex