15-Deoxy-Delta12,14-prostaglandin J2 induces COX-2 expression through Akt-driven AP-1 activation in human breast cancer cells: a potential role of ROS

• Published in: Carcinogenesis (New York) 2008-04, Vol.29 (4), p.688
• Main Authors: Kim, Eun-Hee, Na, Hye-Kyung, Kim, Do-Hee, Park, Sin-Aye, Kim, Ha-Na, Song, Na-Young, Surh, Young-Joon
• Format: Article
• Language: English
• Subjects: Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cell Division - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Cyclooxygenase 2 - genetics; DNA Probes; DNA Replication; Female; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; Transcription Factor AP-1 - metabolism; Transfection
• ISSN: 1460-2180
• DOI: 10.1093/carcin/bgm299

Recent studies suggest that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately expressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains undefined. Here, we report that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), one of the final products of COX-mediated arachidonic acid metabolism, upregulates the expression of COX-2 in the human breast cancer MCF-7 cell line. 15d-PGJ(2)-induced COX-2 expression was mediated by activation of Akt and subsequently activator protein-1 (AP-1). Furthermore, 15d-PGJ(2) formed reactive oxygen species, which led to increased phosphorylation of Akt, DNA binding of AP-1 and expression of COX-2. In contrast to 15d-PGJ(2), 9,10-dihydro-15d-PGJ(2) did not elicit any of effects induced by 15d-PGJ(2) in this study, suggesting that an electrophilic carbon center present in 15d-PGJ(2) is critical for COX-2 expression as well activation of upstream signal transduction induced by this cyclopentenone prostaglandin. Taken together, these observations suggest that 15d-PGJ(2) produced by COX-2 overexpression may function as a positive regulator of COX-2 in human breast cancer MCF-7 cells.