Caveolin-1-mediated suppression of cyclooxygenase-2 via a β-catenin-Tcf/Lef-dependent transcriptional mechanism reduced prostaglandin e2 production and survivin expression
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Rodríguez, Diego A.
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Caveolin-1-mediated suppression of cyclooxygenase-2 via a β-catenin-Tcf/Lef-dependent transcriptional mechanism reduced prostaglandin e2 production and survivin expression
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Abstract
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 -cateninTcf/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 -catenin-Tcf/Lef–
dependent transcription. Finally, PGE2 reduced the coimmunoprecipitation of caveolin-1 with -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 -catenin/Tcf/Lef–dependent transcription of tumor
survival genes including cox-2 itself and survivin.
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URI: https://repositorio.uchile.cl/handle/2250/154713
DOI: 10.1091/mbc.E08-09-0939
ISSN: 10591524
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Molecular Biology of the Cell, Volumen 20, Issue 8, 2018, Pages 2297-2310
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