Ibuprofen Inhibits Activation of Nuclear beta-Catenin in Human Colon Adenomas and Induces the Phosphorylation of GSK-3 beta

Nonselective cyclooxygenase (COX) inhibitors target many of the same cancer-associated molecular pathways as COX-2-specific inhibitors. Although these nonsteroidal anti-inflammatory drugs (NSAIDs) are often associated with gastrointestinal toxicity, there is renewed interest in their use as colorectal cancer (CRC) chemopreventive agents due to the adverse side effects associated with long-term use of selective COX-2 inhibitors. In this study, we investigated the effects of long-term use (up to 25 years) of NSAIDs (ibuprofen or aspirin) on adenoma pathology and beta-catenin-mediated signaling in sporadic human colon adenomas. Although NSAID use did not impact overall adenoma size or degree of dysplasia, it did cause a significant inhibition of nuclear beta-catenin localization, which correlated with suppression of cyclin D1 expression. To further elucidate the effect of these agents in regulating beta-catenin, we treated SW480 colon cancer cells with a panel of NSAIDs and determined their effects on beta-catenin levels and cellular localization. In agreement with our in vivo results, both S-ibuprofen and aspirin were found to decrease total levels of beta-catenin while increasing its phosphorylation. In addition, S-ibuprofen induced both degradation of I kappa B alpha and nuclear localization of NF-kappa B. Despite its nuclear localization, however, the activation of the NF-kappa B target genes, Bcl-2, survivin, and cyclin D1, was suppressed. This reduction in NF-kappa B transcriptional activity may be due to increased phosphorylation of GSK-3 beta following S-ibuprofen treatment. These data suggest that ibuprofen can effectively target both the Wnt/beta-catenin and NF-kappa B pathways, and potentially uncovers a novel mechanism through which NSAIDS may exert their chemopreventive efficacy. Cancer Prev Res; 4(1); 161-71. (C) 2011 AACR.