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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
Author(s) -
Maier Thorsten Jürgen,
Janssen Astrid,
Schmidt Ronald,
Geisslinger Gerd,
Grösch Sabine
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-3274fje
Subject(s) - celecoxib , rofecoxib , cyclooxygenase , chemistry , cancer research , beta catenin , catenin , pharmacology , gsk 3 , lncap , kinase , medicine , wnt signaling pathway , enzyme , biochemistry , biology , cancer cell , signal transduction , cancer
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/β‐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 µM celecoxib, we observed a rapid translocation of β‐catenin from its predominant membrane localization to the cytoplasm. Inhibition of the glycogen‐synthasekinase‐3β (GSK‐3β) by LiCl prevented this celecoxib‐induced translocation, suggesting that phosphorylation of β‐catenin by the GSK‐3β kinase was essential for this release. Furthermore, the cytosolic accumulation was accompanied by a rapid increase of β‐catenin in the nuclei, starting already 30 min after celecoxib treatment. The DNA binding activity of β‐catenin time dependently decreased 2 h after celecoxib treatment. After this cellular reorganization, we observed a caspase‐ and proteasome‐dependent degradation of β‐catenin after 8 h of drug incubation. Celecoxib‐induced β‐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 β‐catenin in human colon carcinoma cells.