Nrf2 as a novel molecular target for chemoprevention

Lee, Jeong-Sang; Surh, Young‐Joon

doi:10.1016/j.canlet.2004.09.042

Cited by 472 publications

(353 citation statements)

References 99 publications

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“…It is now clear that the Nrf2 activity is precisely regulated. According to current thinking, in the resting state, most Nrf2 is sequestered in the cytoplasm through its association with Keap1, which anchors to the cytoskeleton [63,64]. It was found that Keap1 could function as ubiquitin-E3 ligase and mediate the rapid turnover of Nrf2 by proteosomal degradation under normal physiological conditions [42,43].…”

Section: Discussionmentioning

confidence: 99%

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Zhang

Liu

Dickinson

et al. 2006

Free Radical Biology and Medicine

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Abstractγ-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNAV is controlled by promoter 5. Previously we found that GGT mRNAV-2 was responsible for the induction of GGT in rat alveolar epithelial cells by 4-hydroxynonenal (HNE). In the current study, the underlying mechanism was investigated. Reporter deletion and mutation analysis demonstrated that an electrophile-response element (EpRE) in the proximal region of GGT promoter 5 (GP5) was responsible for the basal-and HNE-induced promoter activity. Gel-shift assays showed an increased binding activity of GP5 EpRE after HNE exposure. The nuclear content of NF-E2-related factor 2 (Nrf2) was significantly increased by HNE. The recruitment of Nrf2 to GP5 EpRE after HNE treatment was demonstrated by supershift and chromatin immunoprecipitation assays. The tissue expression pattern of GGT mRNA V was previously unknown. Using polymerase chain reaction, we found that GGT mRNAV-2 was expressed in many tissues in rat. Taken together, GGT mRNAV-2 is widely expressed in rat tissues and its basal and HNE-induced expression is mediated through EpRE/Nrf2 signaling.

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Section: Discussionmentioning

confidence: 99%

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Zhang

Liu

Dickinson

et al. 2006

Free Radical Biology and Medicine

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“…This appears to reflect, in turn, an age-related decline in expression and function of the Nrf2 transcription factor (Suh et al 2004a;Suh et al 2004b;Ungvari et al 2011;Shih and Yen 2007). Nrf2 promotes transcription of a wide array of enzymes which combats oxidative stress and aids the detoxification of mutagenic electrophiles; among these is the ratelimiting enzyme for glutathione synthesis, glutamate cysteine lyase (GCL) (Wild et al 1999;Lee and Surh 2005). Why Nrf2 expression declines with age remains mysterious; a concurrent upregulation of its functional antagonist Keap1 may also contribute to a loss of Nrf2 activity in the elderly (Ungvari et al 2011).…”

Section: Glutathione Levels Decline During Agingmentioning

confidence: 99%

“…Moreover, the expression of GCL can be enhanced by administration of phase 2 inducer chemicals-compounds which disrupt the inhibitory association of Nrf2 with Keap1 (Wild et al 1999;Lee and Surh 2005). Some of these-such as lipoic acid-also boost translation of Nrf2 messenger RNA via an internal ribosome entry sequence (IRES) (Shay et al 2012).…”

Section: Strategies For Boosting Glutathione Synthesismentioning

confidence: 99%

“…(Suh et al 2004a;Suh et al 2004b;Flier et al 2002;Jia et al 2008). Arguably, concurrent administration of lipoic acid and NAC should be a highly effective strategy for amplifying deficient glutathione levels that has the ancillary benefit of increasing the expression of a number of other antioxidant and cytoprotective proteins whose transcription is promoted by Nrf2 (Lee and Surh 2005).…”

Section: Strategies For Boosting Glutathione Synthesismentioning

confidence: 99%

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An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

McCarty

DiNicolantonio

2015

AGE

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Restricted dietary intakes of protein or essential amino acids tend to slow aging and boost lifespan in rodents, presumably because they downregulate IGF-I/ Akt/mTORC1 signaling that acts as a pacesetter for aging and promotes cancer induction. A recent analysis of the National Health and Nutrition Examination Survey (NHANES) III cohort has revealed that relatively low protein intakes in mid-life (under 10 % of calories) are indeed associated with decreased subsequent risk for mortality. However, in those over 65 at baseline, such low protein intakes were associated with increased risk for mortality. This finding accords well with other epidemiology correlating relatively high protein intakes with lower risk for loss of lean mass and bone density in the elderly.

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“…Dithiolethiones induce redox coactivator Ref-1, which enhances AP-1-dependent transcription of c-fos and c-jun (Yao and O'Dwyer, 2003). Dithiolethiones also induce antioxidant-response element (ARE)-regulated genes via dissociation of nuclear transcription factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) from Kelch-like ECH-associated protein 1 (Keap1), which sequesters Nrf2 in the cytoplasm (Lee and Surh, 2005). The activation of these pathways is dependent on oxidation of key thiols in the molecular targets.…”

Section: Introductionmentioning

confidence: 99%

Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

Isenberg

Jia

Field

et al. 2007

British J Pharmacology

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Background and purpose: Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated antiangiogenic properties, we investigated the activities of a new class of anti-inflammatory drugs containing dithiolethione moieties (S-NSAIDs) and S-valproate. Experimental approach: Anti-angiogenic activities of S-NSAIDS, S-valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos. Key results: Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser 78 phosphorylation of hsp27, a known molecular target of anti-angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S-NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H 2 S. In contrast to the parent drugs, S-NSAIDs, S-valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3-dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S-NSAIDs, remarkably, lacked this activity. Conclusions and implication: S-NSAIDs and S-valproate have potent anti-angiogenic activities mediated by their dithiole moieties. The novel properties of S-NSAIDs and S-valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.

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Nrf2 as a novel molecular target for chemoprevention

Cited by 472 publications

References 99 publications

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

Modulation of angiogenesis by dithiolethione‐modified NSAIDs and valproic acid

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