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

Ji Woo Kim, Mei Hua Li, Jung Hee Jang, Hye Kyung Na, Na Young Song, Chan Lee, Jeffrey A. Johnson, Young Joon Surh

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80 Citations (Scopus)

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-Δ12,14-prostaglandin J2 (15d-PGJ2), a terminal dehydration product of prostaglandin D2, is an endogenous ligand of peroxisome proliferator-activated receptor-γ 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-PGJ2 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-PGJ2. Treatment of the PC12 cells with 15d-PGJ2 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-PGJ2-derived induction of HO-1 expression. Moreover, the 15d-PGJ2-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-PGJ2 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.

Original languageEnglish
Pages (from-to)1577-1589
Number of pages13
JournalBiochemical Pharmacology
Volume76
Issue number11
DOIs
Publication statusPublished - 2008 Dec 1

Bibliographical note

Funding Information:
This work was supported by the National Research Laboratory fund and also the grant for the Innovative Drug Research Center (R11-2007-107-0000-0) and Basic Research Program (R01-2007-000-11164-0) provided by the Korea Science and Engineering Foundation, Republic of Korea.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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