title: 15-Deoxy-Delta(12,14)-prostaglandin J(2) rescues PC12 cells from H2O2-induced apoptosis through Nrf2-mediated upregulation of heme oxygenase-1: potential roles of Akt and ERK1/2.
abstract: Oxidative stress induced by reactive oxygen intermediates has been implicated in a variety of human diseases including rheumatoid arthritis and neurodegenerative disorders. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a terminal dehydration product of prostaglandin D(2), is an endogenous ligand of peroxisome proliferator-activated receptor-gamma and exhibits a number of biological activities including the proapoptotic activity. Recent studies have revealed that this cyclopentenone prostaglandin, at non-toxic concentrations, can also exert antiapoptotic or cytoprotective effects. In this study, the underlying mechanisms involved in the protective effects of 15d-PGJ(2) on the H2O2-induced cytotoxicty were explored using cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with H2O2 underwent apoptosis, which was attenuated by pretreatment with non-toxic concentrations of 15d-PGJ(2). Treatment of the PC12 cells with 15d-PGJ(2) resulted in increased nuclear translocation, DNA-binding and transcriptional activity of NF-E2-related factor 2 (Nrf2), leading to upregulation of heme oxygenase-1 (HO-1) expression, which provided an adaptive survival response against the H2O2-derived oxidative cytotoxicity. Transfection of PC12 cells with dominant-negative Nrf2 gene abolished the 15d-PGJ(2)-derived induction of HO-1 expression. Moreover, the 15d-PGJ(2)-mediated increases in Nrf2-ARE binding and ARE luciferase activity were suppressed by the dominant-negative mutation as well as the pharmacological inhibition of Akt/protein kinase B or extracellular signal-regulated kinase 1/2 (ERK1/2). Taken together, these findings suggest that 15d-PGJ(2) augments cellular antioxidant defense capacity through activation of Akt and ERK signal pathways that leads to Nrf2 activation, and subsequently HO-1 induction, thereby protecting the PC12 cells from H2O2-induced oxidative cell death.
authors.affiliation: National Research Laboratory, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea.
authors.forename: Ji-Woo
authors.initials: JW
authors.lastname: Kim
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Li
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Jang
authors.forename: Hye-Kyung
authors.initials: HK
authors.lastname: Na
authors.forename: Na-Young
authors.initials: NY
authors.lastname: Song
authors.forename: Chan
authors.initials: C
authors.lastname: Lee
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016716:PC12 Cells; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3; D015230:Prostaglandin D2