Carcinogenesis Advance Access published online on January 12, 2008
Carcinogenesis, 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
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Gu, Seoul 151-742
# Cancer Research Institute, Seoul National University, Seoul 110-799, South Korea
Address for correspondence:Professor Young-Joon Surh, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea. Phone) +82 2 880-7845; Fax) +82 2 874-9775 E-mail) 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 cyclooxygenases (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 (ROS), 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 over-expression may function as a positive regulator of COX-2 in human breast cancer MCF-7 cells.
Key Words: 15-deoxy-12 • 14-prostaglandin J2 • Akt • AP-1 • cyclooxygenase-2 • reactive oxygen species • MCF-7 cells
Received June 12, 2007; revised November 15, 2007; accepted December 20, 2007.
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  D.-H. Kim, J.-H. Kim, E.-H. Kim, H.-K. Na, Y.-N. Cha, J. H. Chung, and Y.-J. Surh 15-Deoxy-{Delta}12,14-prostaglandin J2 upregulates the expression of heme oxygenase-1 and subsequently matrix metalloproteinase-1 in human breast cancer cells: possible roles of iron and ROS Carcinogenesis, April 1, 2009; 30(4): 645 - 654. [Abstract] [Full Text] [PDF]
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