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Vol. 20, Issue 8, 2297-2310, April 15, 2009

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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

Diego A. Rodriguez^*, Julio C. Tapia, Jaime G. Fernandez^*,, Vicente A. Torres^*, Nicolas Muñoz^*, Daniela Galleguillos^*, Lisette Leyton^*, and Andrew F. G. Quest^*

*Laboratory of Cellular Communication, Fondo de Investigación Avanzada en Areas Prioritarias (FONDAP) Center for Molecular Studies of the Cell (CEMC), Cell Transformation Laboratory, Program of Cellular and Molecular Biology, Facultad de Medicina and Departmento de Cirugía, Hospital Clínico, Universidad de Chile, Santiago, Chile

Submitted September 17, 2008; Revised January 28, 2009; Accepted February 13, 2009
Monitoring Editor: J. Silvio Gutkind

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 β-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 β-catenin-Tcf/Lef–dependent transcription. Finally, PGE₂ 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 PGE₂-induced signaling events linked to β-catenin/Tcf/Lef–dependent transcription of tumor survival genes including cox-2 itself and survivin.

The results reported here have been presented in preliminary form on previous occasions: 22nd Annual Meeting of the Chilean Cell Biology Society, Pucon, Chile, October 5–9, 2008 and 48th Annual Meeting of the American Society for Cell Biology, San Francisco, CA, December 13–17, 2008.

Address correspondence to: Andrew Quest (aquest{at}med.uchile.cl)

Abbreviations used: APC, adenomatous polyposis coli; COX-2, cyclooxygenase-2; GSK-3β, glycogen synthase kinase 3β; IPTG, isopropyl β-D-1-thiogalactopyranoside; PGE₂, prostaglandin E₂; qPCR, quantitative PCR; RT-PCR, reverse transcriptase polymerase chain reaction; TBE, Tcf/Lef-binding element.