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.
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.
Kim
Eun-Hee
EH
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Na
Hye-Kyung
HK
Kim
Do-Hee
DH
Park
Sin-Aye
SA
Kim
Ha-Na
HN
Song
Na-Young
NY
Surh
Young-Joon
YJ
D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015342:DNA Probes; D004261:DNA Replication; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D015342:DNA Probes; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D015230:Prostaglandin D2