Caveolin-1-mediated Suppression of Cyclooxygenase-2 via a beta-catenin-Tcf/Lef-dependent Transcriptional Mechanism Reduced Prostaglandin E-2 Production and Survivin Expression
Augmented expression of cyclooxygenase-2 (COX-2) and enhanced production of prostaglandin E2 (PGE2) are associated with increased tumor cell survival and malignancy. Caveolin-1 is a scaffold protein that has been proposed to function as a tumor suppressor in human cancer cells, although mechanisms underlying this ability remain controversial. Intriguingly, the possibility that caveolin-1 regulates the expression of COX-2 has not been explored. Here we show that augmented caveolin-1 expression in cells with low basal levels of this protein, such as human colon cancer (HT29, DLD-1), breast cancer (ZR75), and embryonic kidney (HEK293T) cells reduced COX-2 mRNA and protein levels and ß-catenin-Tcf/Lef and COX-2 gene reporter activity, as well as the production of PGE2 and cell proliferation. Moreover, COX-2 overexpression or PGE2 supplementation increased levels of the inhibitor of apoptosis protein survivin by a transcriptional mechanism, as determined by PCR analysis, survivin gene reporter assays and Western blotting. Furthermore, addition of PGE2 to the medium prevented effects attributed to caveolin-1-mediated inhibition of ß-catenin-Tcf/Lef-dependent transcription. Finally, PGE2 reduced the coimmunoprecipitation of caveolin-1 with ß-catenin and their colocalization at the plasma membrane. Thus, by reducing COX-2 expression, caveolin-1 interrupts a feedback amplification loop involving PGE2-induced signaling events linked to ß-catenin/Tcf/Lef-dependent transcription of tumor survival genes including cox-2 itself and survivin. © 2009 by The American Society for Cell Biology.
|Título según WOS:||Caveolin-1-mediated Suppression of Cyclooxygenase-2 via a beta-catenin-Tcf/Lef-dependent Transcriptional Mechanism Reduced Prostaglandin E-2 Production and Survivin Expression|
|Título según SCOPUS:||Caveolin-1-mediated suppression of cyclooxygenase-2 via a ?-catenin-Tcf/Lef-dependent transcriptional mechanism reduced prostaglandin e2 production and survivin expression|
|Título de la Revista:||MOLECULAR BIOLOGY OF THE CELL|
|Editorial:||AMER SOC CELL BIOLOGY|
|Fecha de publicación:||2009|
|Página de inicio:||2297|