title: Extracellular signal-regulated kinase is a target of cyclooxygenase-1-peroxisome proliferator-activated receptor-delta signaling in epithelial ovarian cancer.
abstract: 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 delta (PPARdelta) expression and function in EOC. We found that EOC cells express high levels of PPARdelta, and neutralizing PPARdelta function reduces tumor growth in vivo. More interestingly, aspirin, a nonsteroidal anti-inflammatory drug that preferentially inhibits COX-1, compromises PPARdelta 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 PPARdelta can be a target of COX-1, extracellular signal-regulated kinase is a potential target of PPARdelta. 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.
authors.affiliation: Department of Pediatrics, Division of Reproductive and Development Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2678, USA.
authors.forename: Takiko
authors.initials: T
authors.lastname: Daikoku
authors.forename: Susanne
authors.initials: S
authors.lastname: Tranguch
authors.forename: Anindita
authors.initials: A
authors.lastname: Chakrabarty
authors.forename: Dingzhi
authors.initials: D
authors.lastname: Wang
authors.forename: Dineo
authors.initials: D
authors.lastname: Khabele
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Raymond N
authors.initials: RN
authors.lastname: Dubois
authors.forename: Sudhansu K
authors.initials: SK
authors.lastname: Dey
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000473:pathology; D011464:Epoprostenol / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D047494:PPAR delta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D047494:PPAR delta; D011720:Pyrazoles; C115461:SC 560; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001241:Aspirin