Caveolin-1–mediated Suppression of Cyclooxygenase-2 via a β-catenin-Tcf/Lef–dependent Transcriptional Mechanism Reduced Prostaglandin E 2 Production and Survivin Expression

• Published in: Molecular biology of the cell Vol. 20; no. 8; pp. 2297 - 2310
• Main Authors: Rodriguez, Diego A., Tapia, Julio C., Fernandez, Jaime G., Torres, Vicente A., Muñoz, Nicolas, Galleguillos, Daniela, Leyton, Lisette, Quest, Andrew F. G.
• Format: Journal Article
• Language: English
• Published: 15-04-2009
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.e08-09-0939

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 β-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 β-catenin-Tcf/Lef–dependent transcription. Finally, PGE
2
reduced the coimmunoprecipitation of caveolin-1 with β-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 β-catenin/Tcf/Lef–dependent transcription of tumor survival genes including cox-2 itself and survivin.