Mechanism of action of isothiocyanates: The induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2

Changjiang Xu, Xiaoling Yuan, Zui Pan, Guoxiang Shen, Jung Hwan Kim, Siwang Yu, Tin Oo Khor, Wenge Li, Jianjie Ma, Ah Ng Tony Kong

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

The up-regulation of phase II detoxifying and stress-responsive genes is believed to play an important role in cancer prevention, and many natural compounds have been shown to be potent inducers of these genes. Previous studies showed that the antioxidant responsive element (ARE), found in these genes, can be bound by the transcription factor Nrf2, and is responsive to the activation by chemopreventive compounds and by oxidative stress. In the present study, we investigated the roles of extracellular signal-regulated kinase (ERK) and c-Jun-NH2-kinase (JNK) in the regulation of phenethyl isothiocyanate (PEITC)-induced and Nrf2-dependent ARE activity and ARE-driven heme oxygenase-1 (HO-1) gene expression in PC-3 cells. ARE activity and HO-1 expression were strongly increased after treatment with PEITC. PEITC also increased the phosphorylation of ERK1/2 and JNK1/ 2 and caused release of Nrf2 from sequestration by Keap1, and its subsequent translocation into the nucleus. Importantly, Nrf2 was also translocated into the nucleus after transfection with ERK or JNK and that these activated ERK and JNK colocalized with Nrf2 in the nucleus. Activation of ERK and JNK signaling also resulted in the elevation of ARE activity and HO-1 expression. Importantly, PEITC-induced ARE activity was attenuated by inhibition of ERK and JNK signaling. In vitro kinase assays showed that both ERK2 and JNK1 could directly phosphorylate glutathione S-transferase-Nrf2 protein. Taken together, these results strongly suggest a model in which PEITC treatment of PC-3 cells activates ERK and JNK, whixh, in turn, phosphorylate Nrf2 and induce its translocation to the nucleus. Nuclear Nrf2 activates ARE elements and induces expression of stress-responsive genes, including HO-1.

Original languageEnglish (US)
Pages (from-to)1918-1926
Number of pages9
JournalMolecular Cancer Therapeutics
Volume5
Issue number8
DOIs
StatePublished - Aug 2006
Externally publishedYes

Fingerprint

Isothiocyanates
Extracellular Signal-Regulated MAP Kinases
Phosphotransferases
Antioxidants
Phosphorylation
Heme Oxygenase-1
Genes
Glutathione Transferase
Transfection
Oxidative Stress
Transcription Factors
Up-Regulation
phenethyl isothiocyanate
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Mechanism of action of isothiocyanates : The induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2. / Xu, Changjiang; Yuan, Xiaoling; Pan, Zui; Shen, Guoxiang; Kim, Jung Hwan; Yu, Siwang; Khor, Tin Oo; Li, Wenge; Ma, Jianjie; Kong, Ah Ng Tony.

In: Molecular Cancer Therapeutics, Vol. 5, No. 8, 08.2006, p. 1918-1926.

Research output: Contribution to journalArticle

Xu, Changjiang ; Yuan, Xiaoling ; Pan, Zui ; Shen, Guoxiang ; Kim, Jung Hwan ; Yu, Siwang ; Khor, Tin Oo ; Li, Wenge ; Ma, Jianjie ; Kong, Ah Ng Tony. / Mechanism of action of isothiocyanates : The induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 8. pp. 1918-1926.
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abstract = "The up-regulation of phase II detoxifying and stress-responsive genes is believed to play an important role in cancer prevention, and many natural compounds have been shown to be potent inducers of these genes. Previous studies showed that the antioxidant responsive element (ARE), found in these genes, can be bound by the transcription factor Nrf2, and is responsive to the activation by chemopreventive compounds and by oxidative stress. In the present study, we investigated the roles of extracellular signal-regulated kinase (ERK) and c-Jun-NH2-kinase (JNK) in the regulation of phenethyl isothiocyanate (PEITC)-induced and Nrf2-dependent ARE activity and ARE-driven heme oxygenase-1 (HO-1) gene expression in PC-3 cells. ARE activity and HO-1 expression were strongly increased after treatment with PEITC. PEITC also increased the phosphorylation of ERK1/2 and JNK1/ 2 and caused release of Nrf2 from sequestration by Keap1, and its subsequent translocation into the nucleus. Importantly, Nrf2 was also translocated into the nucleus after transfection with ERK or JNK and that these activated ERK and JNK colocalized with Nrf2 in the nucleus. Activation of ERK and JNK signaling also resulted in the elevation of ARE activity and HO-1 expression. Importantly, PEITC-induced ARE activity was attenuated by inhibition of ERK and JNK signaling. In vitro kinase assays showed that both ERK2 and JNK1 could directly phosphorylate glutathione S-transferase-Nrf2 protein. Taken together, these results strongly suggest a model in which PEITC treatment of PC-3 cells activates ERK and JNK, whixh, in turn, phosphorylate Nrf2 and induce its translocation to the nucleus. Nuclear Nrf2 activates ARE elements and induces expression of stress-responsive genes, including HO-1.",
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T2 - The induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2

AU - Xu, Changjiang

AU - Yuan, Xiaoling

AU - Pan, Zui

AU - Shen, Guoxiang

AU - Kim, Jung Hwan

AU - Yu, Siwang

AU - Khor, Tin Oo

AU - Li, Wenge

AU - Ma, Jianjie

AU - Kong, Ah Ng Tony

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