Carcinogenesis Advance Access originally published online on January 12, 2008
Carcinogenesis 2008 29(4):688-695; doi:10.1093/carcin/bgm299
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15-Deoxy-
12,14-prostaglandin J2 induces COX-2 expression through Akt-driven AP-1 activation in human breast cancer cells: a potential role of ROS
1 National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea
2 Cancer Research Institute, Seoul National University, Seoul 110-799, South Korea
* To whom correspondence should be addressed. Tel: +82 2 880 7845; Fax: +82 2 874 9775; Email: surh{at}plaza.snu.ac.kr
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-
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.
Abbreviations: AP-1, activator protein-1; COX-2, cyclooxygenase-2; CRE, cyclic AMP response element; 15d-PGJ2, 15-deoxy-12,14-prostaglandin J2; GSH, reduced glutathione; KD, kinase-dead; MAPK, mitogen-activated protein kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC, N-acetyl-L-cysteine; PBS, phosphate-buffered saline; PPAR
, peroxisome proliferator-activated receptor ; PTEN, phosphatase and tensin homologue deleted on chromosome 10; ROS, reactive oxygen species
Received June 12, 2007; revised November 15, 2007; accepted December 20, 2007.
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