Induction of activation of the antioxidant response element and stabilization of Nrf2 by 3-(3-pyridylmethylidene)-2-indolinone (PMID) confers protection against oxidative stress-induced cell death

Journal Article · Thu Mar 01 00:00:00 EST 2012 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2011.12.027· OSTI ID:22215258

Yao, Jia-Wei ^[1]; Liu, Jing ^[2]; Kong, Xiang-Zhen ^[1]; Zhang, Shou-Guo ^[2]; Wang, Xiao-Hui ^[2]; Yu, Miao; Zhan, Yi-Qun; Li, Wei; Xu, Wang-Xiang ^[2]; Tang, Liu-Jun ^[2]; Ge, Chang-Hui ^[2]; Wang, Lin ^[2]; Li, Chang-Yan ^[2]; Yang, Xiao-Ming ^[1]

---

1. Tianjin University, School of Chemical Engineering and Technology, Department of pharmaceutical engineering, Tianjin 300072 (China)
2. Beijing Institute of Radiation Medicine, Beijing 100850 (China)

The antioxidant response elements (ARE) are a cis-acting enhancer sequence located in regulatory regions of antioxidant and detoxifying genes. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a member of the Cap ‘n’ Collar family of transcription factors that binds to the ARE and regulates the transcription of specific ARE-containing genes. Under oxidative stress, Nrf2/ARE induction is fundamental to defense against reactive oxygen species (ROS) and serves as a key factor in the protection against toxic xenobiotics. 3-(3-Pyridylmethylidene)-2-Indolinone (PMID) is a derivative of 2-indolinone compounds which act as protein kinase inhibitors and show anti-tumor activity. However, the role of PMID in the oxidative stress remains unknown. In the present study, we showed that PMID induced the activation of ARE-mediated transcription, increased the DNA-binding activity of Nrf2 and then up-regulated the expression of antioxidant genes such as HO-1, SOD, and NQO1. The level of Nrf2 protein was increased in cells treated with PMID by a post-transcriptional mechanism. Under CHX treatment, the stability of Nrf2 protein was enhanced by PMID with decreased turnover rate. We showed that PMID reduced the ubiquitination of Nrf2 and disrupted the Cullin3 (Cul3)-Keap1 interaction. Furthermore, cells treated with PMID showed resistance to cytotoxicity by H{sub 2}O{sub 2} and pro-oxidant 6-OHDA. PMID also up-regulated the antioxidant level in BALB/c mice. Taken together, the compound PMID induces the ARE-mediated gene expression through stabilization of Nrf2 protein and activation of Nrf2/ARE pathway and protects against oxidative stress-mediated cell death. -- Highlights: ► PMID up-regulates ARE-mediated antioxidant gene expression in vitro and in vivo. ► PMID enhances the stabilization of Nrf2 protein, decreasing Nrf2 turnover rate. ► PMID disrupted the Cullin3 (Cul3)-Keap1 interaction. ► PMID protects against cell death induced by H{sub 2}O{sub 2} and pro-oxidant 6-OHDA.

• OSTI ID: 22215258
• Journal Information: Toxicology and Applied Pharmacology, Vol. 259, Issue 2; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIOXIDANTS
APOPTOSIS
BENZOQUINONES
DNA
ECR HEATING
GENES
GLUTATHIONE
HEME
HYDROGEN PEROXIDE
IN VITRO
IN VIVO
MICE
NAD
NEOPLASMS
OXIDATION
OXIDIZERS
PHOSPHATES
STABILIZATION
SUPEROXIDE DISMUTASE
TOXICITY
TRANSCRIPTION
TRANSCRIPTION FACTORS
XENOBIOTICS