Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis

doi:10.1016/j.bcp.2008.07.017

Biochemical Pharmacology

Volume 76, Issue 11, 1 December 2008, Pages 1485-1489

https://doi.org/10.1016/j.bcp.2008.07.017 Get rights and content

Abstract

Oxidative stress has been implicated in the etiology of neurodegenerative disease, cancer and aging. Indeed, accumulation of reactive oxygen and nitrogen species generated by inflammatory cells that created oxidative stress is thought to be one of the major factor by which chronic inflammation contributes to neoplastic transformation as well as many other diseases. We have recently reported that mice lacking nuclear factor-erythroid 2-related factor 2 (Nrf2) are more susceptible to dextran sulfate sodium (DSS)-induced colitis and colorectal carcinogenesis. Nrf2 is a basic leucine zipper redox-sensitive transcriptional factor that plays a center role in ARE (antioxidant response element)-mediated induction of phase II detoxifying and antioxidant enzymes. We found that increased susceptibility of Nrf2 deficient mice to DSS-induced colitis and colorectal cancer was associated with decreased expression of antioxidant/phase II detoxifying enzymes in parallel with upregulation of pro-inflammatory cytokines/biomarkers. These findings suggest that Nrf2 may play an important role in defense against oxidative stress possibly by activation of cellular antioxidant machinery as well as suppression of pro-inflammatory signaling pathways. In addition, in vivo and in vitro data generated from our laboratory suggest that many dietary compounds can differentially regulate Nrf2-mediated antioxidant/anti-inflammatory signaling pathways as the first line defense or induce apoptosis once the cells have been damaged. In this review, we will summarize our thoughts on the potential cross-talks between Nrf2 and NFκB pathways. Although the mechanisms involved in the cross-talk between these signaling pathways are still illusive, targeting Nrf2-antioxidative stress signaling is an ideal strategy to prevent or treat oxidative stress-related diseases.

Introduction

Nrf2 is an important cytoprotective transcription factor. When challenged by oxidants or electrophiles, Nrf2 induces the transcription of diverse antioxidant enzymes, phase II detoxification enzymes, phase III efflux transporters. In combine, these cytoprotective genes can rapidly and coordinately neutralize, detoxify and remove those invading xenobiotics. Accumulating evidences show that Nrf2 is also the promising target for cancer chemoprevention.

Section snippets

Nrf2 signaling (I): the hinge and latch model

At unstressed condition, Nrf2 is sequestered in the cytoplasm by a cytosolic repressor Keap1 (Kelch-like ECH-associated protein 1) [1]. Recently, Keap1 is also characterized as a Cullin 3-dependent ubiquitination substrate adaptor protein [2], [3], [4], [5]. So Nrf2 is not only physically sequestered in the cytoplasm, but also constantly degraded. At the oxidative condition, Nrf2 is released from Keap1 repression, translocates to the nucleus, forms heterodimer with small Maf (musculoaponeurotic

Nrf2 signaling (II): graded nuclear translocation of Nrf2

The second question is whether free Nrf2 automatically translocates into the nucleus? The answer is a definite no. Recently we characterized in Nrf2 a nuclear export signal (NES) in the leucine zipper domain (NESzip) [13] and another NES motif located in the Neh5 transactivation domain (NES_TA) [14]. In addition, we also identified a bipartite nuclear localization signal (NLS) in the basic region (bNLS) [13]. It is the combined activities of multiple NLS/NES motifs that determine the subcellular

Nrf2-mediated cancer chemoprevention

Nrf2 is an important anti-neoplastic factor and the key target of cancer chemoprevention. We compared the anti-neoplastic effect between Nrf2 wild type (WT) and knockout (KO) mice in 7,12-dimethylbenz(a)anthracene (DMBA)-12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin carcinogenesis model [16]. Topic application of a single dose DMBA (200 nmol) followed by TPA treatment (8 nmol, twice a week) for 25 weeks elicited significantly higher tumor incidence in Nrf2 KO mice in comparison with WT

Chronic inflammation promotes neoplastic transformation

Accumulated evidence showed that chronic inflammation promotes neoplastic transformation. Recently we developed a chronic inflammation mice model. We used dextran sulfate sodium (DSS) to induce colonic colitis [17]. Feeding of 1% DSS in drinking water for 1 week induce colonic colitis. In comparison with Nrf2 WT mice, the colonic colitis observed in Nrf2 KO mice appeared to be more severe, including lost of colonic crypt, massive infiltration of inflammatory cells and anal bleeding. In

Potential cross-talk between Nrf2 and NFκB pathways

These data obtained from animal studies underlined the possibility that Nrf2-mediated anti-tumorigenic effect may be achieved by activation of antioxidant machinery as well as suppression of pro-inflammatory pathways mediated by NFκB signaling. Previously, we observed that lipopolysaccharide (LPS) induced NFκB activation could be attenuated by diverse Nrf2 activators, such as phenethyl isothiocyanate (PEITC), SFN and curcumin (CUR) [18]. Dietary administrations of SFN and dibenzoylmethane (DBM)

PEITC and curcumin treatments induce apoptotic death

Previously, cancer chemopreventive compound PEITC was reported to be able to delete preneoplastic cells through induction of apoptosis [22], [23]. Treatment of tumeric curcumin was also found to be able to induce apoptosis in prostate cancer cells [24]. Indeed, we observed that treatment of PEITC and curcumin could inhibit the growth of human PC-3 prostate xenografts in nude mice [25]. The growth inhibitory effect may, at least partially, be attributed to induced apoptosis. Using an in situ

Perspectives

Previous MS–MS studies have identified reactive cysteine residues in Keap1, now Nrf2 also seems to possess reactive cysteine(s). What is the functional significance? The existence of reactive cysteines in Nrf2, especially those cysteines located in functional motifs of Nrf2, implies that Nrf2 per se is a redox-sensitive probe. It awaits further experimental examination of the relative sensitivity and functional roles of those cysteine residues, both in Keap1 and in Nrf2.

Acknowledgements

We thank Dr. Jefferson Chan for his general gift of Nrf2 knockout mice. We thank all collaborators in Drs. Allan Conney and C.S. Yang's laboratory. We thank Drs. Hong Li and Tong Liu for their assistance in MS–MS analysis. We thank all current and former members of Dr. Kong's laboratory for their contribution and comment.

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^☆: Supported by NIH Grants CA-073674, CA-094828 and CA-118947.

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Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis☆

Abstract

Introduction

Section snippets

Nrf2 signaling (I): the hinge and latch model

Nrf2 signaling (II): graded nuclear translocation of Nrf2

Nrf2-mediated cancer chemoprevention

Chronic inflammation promotes neoplastic transformation

Potential cross-talk between Nrf2 and NFκB pathways

PEITC and curcumin treatments induce apoptotic death

Perspectives

Acknowledgements

Trends Mol Med

Arch Biochem Biophys

Mol Cell

J Biol Chem

J Biol Chem

Biochim Biophys Acta

The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase

Mol Cell Biol

BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase

Mol Cell Biol

Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2

Mol Cell Biol

Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex

Mol Cell Biol

Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system

Genes Cells

Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model

Mol Cell Biol