The nonsteroidal anti-inflammatory drug, nabumetone, differentially inhibits beta-catenin signaling in the MIN mouse and azoxymethane-treated rat models of colon carcinogenesis.
The mechanisms through which beta-catenin signaling is inhibited during colorectal cancer chemoprevention by nonsteroidal anti-inflammatory agents is incompletely understood. We report that nabumetone decreased uninvolved intestinal mucosal beta-catenin levels in the MIN mouse with a concomitant increase in glycogen synthase kinase (GSK)-3beta levels, an enzyme that targets beta-catenin for destruction. However, in the azoxymethane-treated rat, where beta-catenin is frequently rendered GSK-3beta-insensitive, nabumetone failed to alter beta-catenin levels but did decrease beta-catenin nuclear localization and transcriptional activity as gauged by cyclin D1. In conclusion, we demonstrate that the differential mechanisms for beta-catenin suppression may be determined, at least partly, by GSK-3beta.
Roy
Hemant K
HK
Department of Internal Medicine, Evanston-Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201, USA. h-roy@northwestern.edu
Karolski
William J
WJ
Wali
Ramesh K
RK
Ratashak
Anne
A
Hart
John
J
Smyrk
Thomas C
TC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001397:Azoxymethane; D015153:Blotting, Western; D002074:Butanones / Q000494:pharmacology*; D015820:Cadherins / Q000096:biosynthesis / Q000187:drug effects; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D000077430:Nabumetone; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015534:Trans-Activators / Q000187:drug effects* / Q000378:metabolism; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002074:Butanones; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D002273:Carcinogens; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; D038362:Glycogen Synthase Kinase 3; D000077430:Nabumetone; D001397:Azoxymethane