15-Deoxy-Δ^12,14-prostaglandin J₂ induces COX-2 expression through Akt-driven AP-1 activation in human breast cancer cells: A potential role of ROS

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-Δ^12,14-prostaglandin J₂ (15d-PGJ₂), 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-PGJ₂ -induced COX-2 expression was mediated by activation of Akt and subsequently activator protein-1 (AP-1). Furthermore, 15d-PGJ₂ 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-PGJ₂, 9,10-dihydro-15d-PGJ₂ did not elicit any of effects induced by 15d-PGJ₂ in this study, suggesting that an electrophilic carbon center present in 15d-PGJ₂ 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-PGJ₂ produced by COX-2 overexpression may function as a positive regulator of COX-2 in human breast cancer MCF-7 cells.