The nonsteroidal anti-inflammatory drug, nabumetone, differentially inhibits β-catenin signaling in the MIN mouse and azoxymethane-treated rat models of colon carcinogenesis

The mechanisms through which β-catenin signaling is inhibited during colorectal cancer chemoprevention by nonsteroidal anti-inflammatory agents is incompletely understood. We report that nabumetone decreased uninvolved intestinal mucosal β-catenin levels in the MIN mouse with a concomitant increase in glycogen synthase kinase (GSK)-3β levels, an enzyme that targets β-catenin for destruction. However, in the azoxymethane-treated rat, where β-catenin is frequently rendered GSK-3β-insensitive, nabumetone failed to alter β-catenin levels but did decrease β-catenin nuclear localization and transcriptional activity as gauged by cyclin D1. In conclusion, we demonstrate that the differential mechanisms for β-catenin suppression may be determined, at least partly, by GSK-3β.