Caveolin-1-mediated suppression of cyclooxygenase-2 via a beta-catenin-Tcf/Lef-dependent transcriptional mechanism reduced prostaglandin E2 production and survivin expression.
Augmented expression of cyclooxygenase-2 (COX-2) and enhanced production of prostaglandin E(2) (PGE(2)) 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 beta-catenin-Tcf/Lef and COX-2 gene reporter activity, as well as the production of PGE(2) and cell proliferation. Moreover, COX-2 overexpression or PGE(2) 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 PGE(2) to the medium prevented effects attributed to caveolin-1-mediated inhibition of beta-catenin-Tcf/Lef-dependent transcription. Finally, PGE(2) reduced the coimmunoprecipitation of caveolin-1 with beta-catenin and their colocalization at the plasma membrane. Thus, by reducing COX-2 expression, caveolin-1 interrupts a feedback amplification loop involving PGE(2)-induced signaling events linked to beta-catenin/Tcf/Lef-dependent transcription of tumor survival genes including cox-2 itself and survivin.
Mesh Terms:
Breast Neoplasms, Cadherins, Caveolin 1, Cell Line, Tumor, Cell Membrane, Cell Nucleus, Cell Proliferation, Colonic Neoplasms, Cyclooxygenase 2, Dinoprostone, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Inhibitor of Apoptosis Proteins, Lymphoid Enhancer-Binding Factor 1, Microtubule-Associated Proteins, Models, Biological, Protein Transport, RNA, Messenger, Transcription, Genetic, beta Catenin
Breast Neoplasms, Cadherins, Caveolin 1, Cell Line, Tumor, Cell Membrane, Cell Nucleus, Cell Proliferation, Colonic Neoplasms, Cyclooxygenase 2, Dinoprostone, Down-Regulation, Gene Expression Regulation, Neoplastic, Humans, Inhibitor of Apoptosis Proteins, Lymphoid Enhancer-Binding Factor 1, Microtubule-Associated Proteins, Models, Biological, Protein Transport, RNA, Messenger, Transcription, Genetic, beta Catenin
Mol. Biol. Cell
Date: Apr. 01, 2009
PubMed ID: 19244345
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