title: Targeting the beta-catenin/APC pathway: a novel mechanism to explain the cyclooxygenase-2-independent anticarcinogenic effects of celecoxib in human colon carcinoma cells.
abstract: 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.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt, Germany.
authors.forename: Thorsten Jürgen
authors.initials: TJ
authors.lastname: Maier
authors.forename: Astrid
authors.initials: A
authors.lastname: Janssen
authors.forename: Ronald
authors.initials: R
authors.lastname: Schmidt
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Sabine
authors.initials: S
authors.lastname: Grösch
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000032:analysis; D020169:Caspases / Q000502:physiology; D000068579:Celecoxib; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000502:physiology*; D004247:DNA / Q000378:metabolism; D005480:Flurbiprofen / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D007783:Lactones / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D051820:TCF Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D015820:Cadherins; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D051820:TCF Transcription Factors; D051176:beta Catenin; C116926:rofecoxib; D005480:Flurbiprofen; D004247:DNA; D051546:Cyclooxygenase 2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; D000068579:Celecoxib