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Targeting the beta-catenin/APC pathway: a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells.

Maier TJ, Janssen A, Schmidt R, Geisslinger G, Grösch S

Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt, Germany.

Celecoxib, a cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drug, is a new anticarcinogenic agent. Its antitumor effects depend on the one hand on its COX-2-inhibiting potency, but on the other hand on COX-2-independent mechanisms, which until now have not been fully understood. Here, we investigated whether celecoxib has an impact on the APC/beta-catenin pathway, which has been shown to play a pivotal role in the development of various cancers, especially of the colon. After only 2 h of treatment of human Caco-2 colon carcinoma cells with 100 muM celecoxib, we observed a rapid translocation of beta-catenin from its predominant membrane localization to the cytoplasm. Inhibition of the glycogen-synthase-kinase-3beta (GSK-3beta) by LiCl prevented this celecoxib-induced translocation, suggesting that phosphorylation of beta-catenin by the GSK-3beta kinase was essential for this release. Furthermore, the cytosolic accumulation was accompanied by a rapid increase of beta-catenin in the nuclei, starting already 30 min after celecoxib treatment. The DNA binding activity of beta-catenin time dependently decreased 2 h after celecoxib treatment. After this cellular reorganization, we observed a caspase- and proteasome-dependent degradation of beta-catenin after 8 h of drug incubation. Celecoxib-induced beta-catenin degradation was also observed in various other tumor cell lines (HCT-116, MCF-7, and LNCAP) but was not seen after treatment of Caco-2 cells with either the anticarcinogenic nonsteroidal anti-inflammatory drug R-flurbiprofen or the highly COX-2-selective inhibitor rofecoxib. These findings indicate that the anticarcinogenic effects of celecoxib can be explained, at least partly, by an extensive degradation of beta-catenin in human colon carcinoma cells.

Published 29 July 2005 in FASEB J, 19(10): 1353-5.
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