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Extracellular Signal-Regulated Kinase Is a Target of Cyclooxygenase-1-Peroxisome Proliferator-Activated Receptor- Signaling in Epithelial Ovarian Cancer

Departments of ¹ Pediatrics, ² Cell and Developmental Biology, ³ Medicine, and ⁴ Pharmacology, Division of Reproductive and Development Biology, Vanderbilt University Medical Center; ⁵ Department of Obstetrics and Gynecology, Meharry Medical College, Nashville, Tennessee; and ⁶ Massachusetts General Hospital Center for Cancer Research, Harvard Medical School, Charlestown, Massachusetts

Requests for reprints: Sudhansu K. Dey, Division of Reproductive and Developmental Biology, Vanderbilt University, Nashville, TN 37232-2678. Phone: 615-322-8642; Email: sk.dey{at}vanderbilt.edu.

The underlying causes of epithelial ovarian cancer (EOC) are unclear, and treatment options for patients with advanced disease are limited. There is evidence that the use of nonsteroidal anti-inflammatory drugs is associated with decreased risk of developing EOC. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase (COX)-1 and COX-2, which catalyze prostaglandin biosynthesis. We previously showed that mouse and human EOCs have increased levels of COX-1, but not COX-2, and a COX-1–selective inhibitor, SC-560, attenuates prostaglandin production and tumor growth. However, the downstream targets of COX-1 signaling in EOC are not yet known. To address this question, we evaluated peroxisome proliferator-activated receptor (PPAR) expression and function in EOC. We found that EOC cells express high levels of PPAR, and neutralizing PPAR function reduces tumor growth in vivo. More interestingly, aspirin, a nonsteroidal anti-inflammatory drug that preferentially inhibits COX-1, compromises PPAR function and cell growth by inhibiting extracellular signal-regulated kinases 1/2, members of the mitogen-activated protein kinase family. Our study, for the first time, shows that whereas PPAR can be a target of COX-1, extracellular signal-regulated kinase is a potential target of PPAR. The ability of aspirin to inhibit EOC growth in vivo is an exciting finding because of its low cost, lack of cardiovascular side effects, and availability. [Cancer Res 2007;67(11):5285–92]

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