The see-saw of Keap1-Nrf2 pathway in cancer

Pandey, Poorti; Singh, Alok Kumar; Singh, Manjeet; Tewari, Mallika; Shukla, H. S.; Gambhir, Indrajeet Singh

doi:10.1016/j.critrevonc.2017.02.006

Cited by 53 publications

(43 citation statements)

References 97 publications

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“…Activation of the NRF2 system is complex and can follow canonical and non-canonical pathways. A difficulty in identifying activators and inhibitors of NRF2 or KEAP1 as modulators of inflammation and potential protectors against oxidative stress and carcinogenesis, is the dual nature of the NRF2-KEAP1 protein-protein interaction [26,[59][60][61][62]. Generally, activation of NRF2 has been viewed as therapeutic, but recent evidence has suggested that this event can be pro-oncogenic as well, depending on the context of NRF2 activation [62].…”

Section: Activators Of Nrf2mentioning

confidence: 99%

Potential Applications of NRF2 Modulators in Cancer Therapy

et al. 2020

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The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

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Section: Activators Of Nrf2mentioning

confidence: 99%

Potential Applications of NRF2 Modulators in Cancer Therapy

et al. 2020

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“…Consequently, cells with low levels of NRF2 and elevated ROS are at risk for neurodegeneration, cardiovascular disease, and chronic inflammation (4,7,8,(23)(24)(25)(26)(27). In contrast, high NRF2 activity leads to cellular resiliency in the face of various stressors, including ROS, genotoxic stress, and metabolic stress (3,9,25,28). Thus, mutations and alterations that increase NRF2 activity contribute to cancer progression and the development of chemoand radioresistance (29).…”

Section: Keap1-nrf2 Signalingmentioning

confidence: 99%

“…Many studies suggest therapeutic applications for NRF2 inducers in the prevention of cancer as well as for the treatment of neurodegenerative disorders and chronic inflammation (3,7,9,10,23,26,28,(113)(114)(115)(116)(117). NRF2 small-molecule inducers are thought to inactivate KEAP1 function through degradation of KEAP1 protein, slowed KEAP1 conformational cycling, covalent modifications of KEAP1, or through dissociation of the KEAP1-NRF2 complex, resulting in NRF2 stabilization and transcriptional activity (7,118,119).…”

Section: Clinical Applications Of Nrf2 In the Context Of Cancer Prevementioning

confidence: 99%

NRF2 Activation in Cancer: From DNA to Protein

et al. 2019

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The Cancer Genome Atlas catalogued alterations in the Kelch-like ECH-associated protein 1 and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in 6.3% of patient samples across 226 studies, with significant enrichment in lung and upper airway cancers. These alterations constitutively activate NRF2-dependent gene transcription to promote many of the cancer hallmarks, including cellular resistance to oxidative stress, xenobiotic efflux, proliferation, and metabolic reprogramming. Almost universally, NRF2 activity strongly associates with poor patient prognosis and chemo-and radioresistance. Yet to date, FDA-approved drugs targeting NRF2 activity in cancer have not been realized.Here, we review various mechanisms that contribute to NRF2 activation in cancer, organized around the central dogma of molecular biology (i) at the DNA level with genomic and epigenetic alterations, (ii) at the RNA level including differential mRNA splicing and stability, and (iii) at the protein level comprising altered posttranslational modifications and protein-protein interactions. Ultimately, defining and understanding the mechanisms responsible for NRF2 activation in cancer may lead to novel targets for therapeutic intervention.

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“…Several studies have reported an increased expression of NRF2 in cancers compared to normal cells, with this being one of the chemoprotective roles of NRF2 in cancers [85,[187][188][189][190][191][192] . Evidence indicates that a dysregulated NRF2/KEAP1 system, for example KEAP1 mutation [76,193] or NRF2 mutation [194] , can be responsible for NRF2 overexpression in cancers leading to enhanced cellular proliferation and chemores istance [76,187,[193][194][195] . NRF2 tends to be overexpressed in cancers when it is freed from KEAP1 anchoring in the cytoplasm at the oxidative state and then translocates to the nucleus, where it heterodimerizes with sMAF and binds to ARE.…”

Section: Role Of Nrf2 In Cancer: Dysregulation-consequences-drug Resimentioning

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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The see-saw of Keap1-Nrf2 pathway in cancer

Cited by 53 publications

References 97 publications

Potential Applications of NRF2 Modulators in Cancer Therapy

Potential Applications of NRF2 Modulators in Cancer Therapy

NRF2 Activation in Cancer: From DNA to Protein

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

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