The emerging role of the Nrf2–Keap1 signaling pathway in cancer

Jaramillo, Melba C.; Zhang, Donna D.

doi:10.1101/gad.225680.113

Cited by 1,134 publications

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References 139 publications

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“…The NRF2/KEAP1 axis is an integrated redox-sensitive signaling system that regulates 1%-10% of human genes. 3 Notably, an oncogenic role of NRF2 activation has recently been proposed, based on the finding that its overexpression and/or mutation takes place in many human cancers, including HCC, 5,24,25 and that cancers with high NRF2 levels are associated with poor prognosis. 26,27 However, as pointed out by Sporn and Liby, whether NRF2 plays a pro-or an antitumorigenic role in premalignant lesions or early malignancy is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…2 It is a master transcriptional activator of genes encoding enzymes that protect cells from oxidative stress and xenobiotics by induction of transcriptional regulation of several antioxidant enzymatic pathways and various drug efflux pumps and members of the multidrug resistance protein family. 3 It is negatively regulated and targeted to proteosomal degradation by KEAP1. 4 It was reported in several studies that either loss of NRF2-KEAP1 interaction or point mutations in the KEAP1 or NRF2 gene are often associated with primary tumors.…”

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confidence: 99%

“…4 It was reported in several studies that either loss of NRF2-KEAP1 interaction or point mutations in the KEAP1 or NRF2 gene are often associated with primary tumors. 3 As for human HCC, two recent studies using whole-exome sequencing have revealed mutations of either NRF2 (6.4%) or KEAP1 (8%), 5,6 suggesting that dysregulation of this pathway may play a relevant role in a subset of human HCCs. Dysregulation of the Nrf2/Keap1 pathway, monitored through analysis of the expression profile of HCC, has also been described in two mouse models where tumors developed in the liver of transforming growth factor-a-c-myc double knockout or in the liver of mice subjected to treatment with diethylnitrosamine plus phenobarbital.…”

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Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

et al. 2015

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Hepatocellular carcinoma (HCC) develops through a multistage process, but the nature of the molecular changes associated with the different steps, the very early ones in particular, is largely unknown. Recently, dysregulation of the NRF2/KEAP1 pathway and mutations of these genes have been observed in experimental and human tumors, suggesting their possible role in cancer development. To assess whether Nrf2/Keap1 mutations are early or late events in HCC development, we investigated their frequency in the rat Resistant Hepatocyte model, consisting of the administration of diethylnitrosamine followed by a brief exposure to 2-acetylaminofluorene. This model enables the dissection of all stages of hepatocarcinogenesis. We found that Nrf2/Keap1 mutations were present in 71% of early preneoplastic lesions and in 78.6% and 59.3% of early and advanced HCCs, respectively. Mutations of Nrf2 were more frequent, missense, and located in the Nrf2-Keap1 binding region. Mutations of Keap1 occurred at a much lower frequency in both preneoplastic lesions and HCCs and were mutually exclusive with those of Nrf2. Functional in vitro and in vivo studies showed that Nrf2 silencing inhibited the ability of tumorigenic rat cells to grow in soft agar and to form tumors. Unlike Nrf2 mutations, those of Ctnnb1, which are frequent in human HCC, were a later event as they appeared only in fully advanced HCCs (18.5%). Conclusion: In the Resistant Hepatocyte model of hepatocarcinogenesis the onset of Nrf2 mutations is a very early event, likely essential for the clonal expansion of preneoplastic hepatocytes to HCC, while Ctnnb1 mutations occur only at very late stages. Moreover, functional experiments demonstrate that Nrf2 is an oncogene critical for HCC progression and development. (HEPATOLOGY 2015;62:851-862) See Editorial on Page 677 H epatocellular carcinoma (HCC) is the third most frequent cause of cancer-related deaths worldwide. 1 Unfortunately, our knowledge of the genomic alterations implicated in HCC initiation and progression is still fragmentary. Moreover, different from other solid tumors, no driving genetic alteration to which tumor cells are addicted and that can be effectively targeted has ever been identified. In this scenario, HCC is probably one of the tumor types where a more complete understanding of the underlying genetic alterations could have a major impact on the development of new treatment strategies. Also known as NFE2L2, NRF2 is of particular interest as conflicting results have been reported concerning the role of the NRF2/KEAP1 pathway in cancer development. 2 It is a master transcriptional activator of genes encoding enzymes that protect cells from oxidative stress and

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

et al. 2015

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“…In this context, the development of Nrf2 inhibitors is challenging for cancer treatment. Discovery of the dual role of Nrf2 enabled scientists to understand the Nrf2 signalling in cancer and development of pharmacological compounds targeting Nrf2 for the prevention of cancer and treatment (reviewed in Jaramillo and Zhang 2013). The maintenance of proper homeostatic conditions by the development of Nrf2 inhibitors/activators is a vital therapeutic strategy.…”

Section: Role Of the Nrf2-keap1 Pathway In Cancermentioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

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The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

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“…A considerable number of studies have demonstrated that Nrf2 signaling protects cells from many hazardous stimuli, such as radiation, invading pathogens and foreign chemicals (e.g. drugs through therapeutic interventions and environmental toxicants) [3][4][5]. Nrf2 directly targets a battery of roughly 250 genes responsible for a wide array of cellular antioxidant responses and detoxification processes, e.g.…”

Section: Introductionmentioning

confidence: 99%

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

Gao

Liu

Chen

et al. 2016

Free Radical Biology and Medicine

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The emerging role of the Nrf2–Keap1 signaling pathway in cancer

Cited by 1,134 publications

References 139 publications

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

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