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15-Deoxy-Δ12,14-prostaglandin J2 rescues PC12 cells from H2O2-induced apoptosis through Nrf2-mediated upregulation of heme oxygenase-1: Potential roles of Akt and ERK1/2

Cited 74 time in Web of Science Cited 79 time in Scopus
Authors
Kim, Ji-Woo; Li, Mei-Hua; Jang, Jung-Hee; Na, Hye-Kyung; Song, Na-Young; Lee, Chan; Johnson, Jeffrey A.; Surh, Young-Joon
Issue Date
2008-12
Citation
Biochemical Pharmacology, Vol.76 No.11, pp.1577-1589
Keywords
15-Deoxy-Delta(12,14)-prostaglandin J(2)Heme oxygenase-1Nrf2Antioxidant response elementsCyclopentenone prostaglandin
Abstract
Oxidative stress induced by reactive oxygen intermediates has been implicated in a variety of human diseases including rheumatoid arthritis and neuro degenerative 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 H(2)O(2)-induced cytotoxicty were explored using cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with H(2)O(2) 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 H(2)O(2)-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 H(2)O(2)-induced oxidative cell death. (c) 2008 Published by Elsevier Inc.
ISSN
0006-2952
URI
https://hdl.handle.net/10371/172608
DOI
https://doi.org/10.1016/j.bcp.2008.08.007
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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