Abstract
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.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Azoxymethane
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Blotting, Western
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Butanones / pharmacology*
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Cadherins / biosynthesis
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Cadherins / drug effects
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Carcinogens
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / prevention & control*
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Cyclin D1 / biosynthesis
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Cyclin D1 / drug effects
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Cytoskeletal Proteins / drug effects*
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Cytoskeletal Proteins / metabolism
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Disease Models, Animal
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Glycogen Synthase Kinase 3 / biosynthesis
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Glycogen Synthase Kinase 3 / drug effects
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Immunohistochemistry
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Male
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Mice
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Nabumetone
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Rats
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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Trans-Activators / drug effects*
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Trans-Activators / metabolism
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beta Catenin
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Butanones
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CTNNB1 protein, mouse
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Cadherins
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Carcinogens
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Ctnnb1 protein, rat
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Cytoskeletal Proteins
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Trans-Activators
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beta Catenin
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Cyclin D1
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Glycogen Synthase Kinase 3
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Nabumetone
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Azoxymethane