title: 15-Deoxy-Δ12,14-prostaglandin J2 induces expression of 15-hydroxyprostaglandin dehydrogenase through Elk-1 activation in human breast cancer MDA-MB-231 cells.
abstract: Overproduction of prostaglandin E2 (PGE2) has been reported to be implicated in carcinogenesis. The intracellular level of PGE2 is maintained not only by its biosynthesis, but also by inactivation/degradation. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the conversion of oncogenic PGE2 to a biologically inactive keto metabolite. In the present study, we demonstrate that 15-deoxy-Δ(12,14)-prostaglandin J2 (15 d-PGJ2), one of the terminal products of cyclooxygenase-2, updregulates the expression and the activity of 15-PGDH in human breast cancer MDA-MB-231 cells. By using deletion constructs of the 15-PGDH promoter, we have found that E-twenty six (Ets) is the most essential determinant for 15-PGDH induction. 15 d-PGJ2 induced phosphorylation of Elk-1, one of Ets transcription factor family members, in the nucleus. Knockdown of Elk-1 abolished the ability of 15 d-PGJ2 to upregulate 15-PGDH expression. Furthermore, 15 d-PGJ2-mediated activation of Elk-1 was found to be dependent on activation of extracellular-signal related kinase (ERK) 1/2. Treatment of U0126, a pharmacological inhibitor of MEK1/2-ERK, abolished phosphorylation and DNA binding of Elk-1 as well as 15-PGDH induction in 15 d-PGJ2-treated MDA-MB-231 cells. Moreover, 15 d-PGJ2 generated reactive oxygen species (ROS), which contribute to the expression of 15-PGDH as well as phosphorylation of ERK1/2 and Elk-1. 15 d-PGJ2 inhibited the migration of MDA-MB-231 cells, which was attenuated by transient transfection with 15-PGDH siRNA. Taken together, these findings suggest that 15 d-PGJ2 induces the expression of 15-PGDH through ROS-mediated activation of ERK1/2 and subsequently Elk-1 in the MDA-MB-231 cells, which may contribute to tumor suppressive activity of this cyclopentenone prostaglandin.
authors.affiliation: Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Hye-Rim
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Ha-Na
authors.initials: HN
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon, South Korea.
authors.forename: Kyu
authors.initials: K
authors.lastname: Lim
authors.affiliation: Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.affiliation: Department of Food and Nutrition, College of Human Ecology, Sungshin Women's University, Seoul 142-732, South Korea. Electronic address: nhkdec28@gmail.com.
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Na
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis* / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002070:Butadienes; C494112:ELK1 protein, human; D009570:Nitriles; D017382:Reactive Oxygen Species; C113580:U 0126; D050807:ets-Domain Protein Elk-1; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015230:Prostaglandin D2
keywords: 15-Deoxy-Δ(12,14)-prostaglandin J(2); 15-Hydroxyprostaglandin dehydrogenase; Breast cancer; Elk-1; ROS