Nrf2: bane or blessing in cancer?

Xiang, Mingjun; Namani, Akhileshwar; Wu, Shijin; Wang, Xiaoli

doi:10.1007/s00432-014-1627-1

Cited by 56 publications

(42 citation statements)

References 105 publications

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“…Despite intense scrutiny in cancer research studies, the precise mechanisms that control Nrf2 translocation remain poorly understood. 54 It is therefore difficult to propose a mechanism by which BDNF controls the Nrf2 pathway. Nevertheless, we have found that BDNF tonically induces Nrf2 translocation into the nucleus under basal conditions, thereby constantly activating antioxidant mechanisms.…”

Section: Upstream Regulation Of Nrf2mentioning

confidence: 99%

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

et al. 2016

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Stressful life events produce a state of vulnerability to depression in some individuals. The mechanisms that contribute to vulnerability to depression remain poorly understood. A rat model of intense stress (social defeat (SD), first hit) produced vulnerability to depression in 40% of animals. Only vulnerable animals developed a depression-like phenotype after a second stressful hit (chronic mild stress). We found that this vulnerability to depression resulted from a persistent state of oxidative stress, which was reversed by treatment with antioxidants. This persistent state of oxidative stress was due to low brain-derived neurotrophic factor (BDNF) levels, which characterized the vulnerable animals. We found that BDNF constitutively controlled the nuclear translocation of the master redox-sensitive transcription factor Nrf2, which activates antioxidant defenses. Low BDNF levels in vulnerable animals prevented Nrf2 translocation and consequently prevented the activation of detoxifying/antioxidant enzymes, ultimately resulting in the generation of sustained oxidative stress. Activating Nrf2 translocation restored redox homeostasis and reversed vulnerability to depression. This mechanism was confirmed in Nrf2-null mice. The mice displayed high levels of oxidative stress and were inherently vulnerable to depression, but this phenotype was reversed by treatment with antioxidants. Our data reveal a novel role for BDNF in controlling redox homeostasis and provide a mechanistic explanation for post-stress vulnerability to depression while suggesting ways to reverse it. Because numerous enzymatic reactions produce reactive oxygen species that must then be cleared, the finding that BDNF controls endogenous redox homeostasis opens new avenues for investigation.

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Section: Upstream Regulation Of Nrf2mentioning

confidence: 99%

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

et al. 2016

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“…This is based on the dissociation of NRF2 from KEAP1 in the cytoplasm leading to the translocation of NRF2 into the nucleus where it dimerizes with sMAF proteins, and then binds to ARE-carrying promoters to subsequently initiate the gene expression of cytoprotective and detoxifying enzymes [60,66] . The activation of the phosphoinositide 3-kinases (PI3K)/Akt signalling pathway and stresses on the endoplasmic reticulum are some of the mechanisms that can lead to nuclear accumulation of NRF2 and increased ARE-driven gene expression [60,67,68] . The non-canonical interacts with NRF2 in the cytosol, promoting its polyubiquitylation and subsequent proteasomal degradation by the substrate adaptor for cullinbased E3 ubiquitin ligase complex, resulting in little NRF2 that is sufficient for the maintenance of cellular homeostasis or absence of NRF2 transactivation; B: In contrast, under oxidative stress conditions, the binding of KEAP1 to NRF2 is greatly impaired to compromise the likelihood of NRF2 ubiquitylation.…”

Section: Nrf2 Signalling Pathway and Regulationmentioning

confidence: 99%

Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies

Paramasivan¹,

Kankia²,

Langdon³

et al. 2019

CDR

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Nuclear factor E2-related factor 2 (NRF2), a transcription factor, is a master regulator of an array of genes related to oxidative and electrophilic stress that promote and maintain redox homeostasis. NRF2 function is well studied in in vitro, animal and general physiology models. However, emerging data has uncovered novel functionality of this transcription factor in human diseases such as cancer, autism, anxiety disorders and diabetes. A key finding in these emerging roles has been its constitutive upregulation in multiple cancers promoting pro-survival phenotypes. The survivability pathways in these studies were mostly explained by classical NRF2 activation involving KEAP-1 relief and transcriptional induction of reactive oxygen species (ROS) neutralizing and cytoprotective drug-metabolizing enzymes (phase I, II, III and 0). Further, NRF2 status and activation is associated with lowered cancer therapeutic efficacy and the eventual emergence of therapeutic resistance. Interestingly, we and others have provided further evidence of direct NRF2 regulation of anticancer drug targets like receptor tyrosine kinases and DNA damage and repair proteins and kinases with implications for therapy outcome. This novel finding demonstrates a renewed role of NRF2 as a key modulatory factor informing anticancer therapeutic outcomes, which extends beyond its described classical role as a ROS regulator. This review will provide a knowledge base for these emerging roles of NRF2 in anticancer therapies involving feedback and feed forward models and will consolidate and present such findings in a systematic manner. This places NRF2 as a key determinant of action, effectiveness and resistance to anticancer therapy.

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“…Persistent, excess Nrf2 activation, such as by Keap1 knockout, has been associated in laboratory studies with (11,46,109) Cancer (63, 67, 109) Heart disease (48,72) Heart disease (70) Liver disease (56,57) Liver disease (110,111) Viruses (59,112,113) Viruses (58) Lung disorders (36,(51)(52)(53)(54)(55) Atherosclerosis (114) Parkinson's disease (38)(39)(40) Huntington's disease (41,42) Amyotrophic lateral sclerosis (43) Multiple sclerosis (44,45) Diabetes (47) Kidney diseases (49,50) Nrf2, nuclear factor erythroid 2-related factor 2.…”

Section: Nrf2 and Reductive Stressmentioning

confidence: 99%

Role of the Nrf2 signaling system in health and disease

Hybertson

Gao

2014

Clinical Genetics

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A key component of cytoprotective gene regulation is the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), also known as nuclear factor erythroid 2-like 2, from the gene NFE2L2. Under normal conditions, Nrf2 in the cell is targeted for proteasomal degradation by its inhibitor Kelch-like ECH-associated inhibitor 1 (Keap1). When stimulated by oxidative stress, electrophiles, or kinase activation, conformational changes in the Nrf2-Keap1 complex inhibit proteasomal degradation of Nrf2, facilitating an increase in the amount of Nrf2 that binds to antioxidant response element sequences in the promoter regions of a variety of antioxidant, detoxification, and metabolic control genes. Nrf2 activation is mostly associated with beneficial cytoprotective gene regulation, but it can also have deleterious effects. For example, gene mutations in some types of cancers can lead to constitutive activation of Nrf2 and give the tumor cells growth advantages and increased drug resistance. Because cases exist where Nrf2/Keap1/ARE signaling is either too low or too high, there is great interest in the development of both Nrf2 activators and Nrf2 inhibitors as the basis of new therapies.

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Nrf2: bane or blessing in cancer?

Abstract: This review aims to rationalize the existing functions of Nrf2 in chemoprevention and tumorigenesis, as well as the somatic mutations of Nrf2 and Keap1 in cancer and Nrf2 cross talk with miRNAs. This review also discusses the future challenges in Nrf2 research.

Cited by 56 publications

References 105 publications

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

Nrf2-dependent persistent oxidative stress results in stress-induced vulnerability to depression

Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies

Role of the Nrf2 signaling system in health and disease

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