The Keap1-Nrf2 system in cancers: Stress response and anabolic metabolism

Department of Respiratory Medicine, Tohoku University Graduate School of Medicine Sendai, Japan.
Frontiers in Oncology 12/2012; 2(article 200):200. DOI: 10.3389/fonc.2012.00200
Source: PubMed

ABSTRACT The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] pathway plays a central role in the protection of cells against oxidative and xenobiotic stresses. Nrf2 is a potent transcription activator that recognizes a unique DNA sequence known as the antioxidant response element (ARE). Under normal conditions, Nrf2 binds to Keap1 in the cytoplasm, resulting in proteasomal degradation. Following exposure to electrophiles or reactive oxygen species, Nrf2 becomes stabilized, translocates into the nucleus, and activates the transcription of various cytoprotective genes. Increasing attention has been paid to the role of Nrf2 in cancer cells because the constitutive stabilization of Nrf2 has been observed in many human cancers with poor prognosis. Recent studies have shown that the antioxidant and detoxification activities of Nrf2 confer chemo- and radio-resistance to cancer cells. In this review, we provide an overview of the Keap1-Nrf2 system and discuss its role under physiological and pathological conditions, including cancers. We also introduce the results of our recent study describing Nrf2 function in the metabolism of cancer cells. Nrf2 likely confers a growth advantage to cancer cells through enhancing cytoprotection and anabolism. Finally, we discuss the possible impact of Nrf2 inhibitors on cancer therapy.

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Available from: Yoichiro Mitsuishi, Mar 05, 2015
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    • "While NRF2 decreases tumor susceptibility in most carcinogenesis models, constitutive activation of NRF2 may enhance tumor cell proliferation and/or confer drug resistance in lung, pancreatic as well as colorectal cancer cells (Arlt et al. 2013; Bryan et al. 2013; Duong et al. 2014b; Homma et al. 2009; Hong et al. 2010; Lister et al. 2011; Mitsuishi et al. 2012; Niture et al. 2014; Singh et al. 2008; Storr et al. 2013; Yamadori et al. 2012). Indeed, NRF2 is up-regulated in many types of tumors through somatic mutations that block KEAP1-dependent regulation of NRF2 stability (Mitsuishi et al. 2012; Niture et al. 2014; Storr et al. 2013). Targeting NRF2 either by RNA interference or by small molecules inhibited tumor growth and increased efficacy of chemotherapy (Singh et al. 2008) or EGF-driven proliferation (Yamadori et al. 2012) in non-small cell lung cancer models and reduced the proliferation and drug-resistance in human lung cancer cells (Homma et al. 2009) or human pancreatic cancer cells (Arlt et al. 2013; Duong et al. 2014b; Hong et al. 2010; Lister et al. 2011). "
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    ABSTRACT: NRF2 is a nuclear transcription factor activated in response to oxidative stress and related with metabolizing of xenotoxic materials and ABC transporter mediated drug resistance. We studied the expression of mRNAs under the siRNA-mediated knockdown of NRF2 and tBHQ-treated condition in AsPC-1 metastatic pancreatic cancer cell line to understand the AsPC-1 specific role(s) of NRF2 and further to investigate the relationship between drug resistance and metastatic plasticity and mobility of AsPc1. Here we show that the genes of aldo–keto reductases, cytochrome P450 family, aldehyde dehydrogenase, thioredoxin reductase, ABC transporter and epoxide hydrolase responsible for drug metabolism or oxidative stress concisely responded to NRF2 stabilization and knockdown of NRF2. In addition the expression of PIR, a candidate of oncogene and KISS1, a suppressor of metastasis were affected by NRF2 stabilization and knockdown. Our result provide comprehensive understanding of NRF2 target genes of drug response, oxidative stress response and metastasis in AsPc-1 metastatic pancreatic cancer cell line. Electronic supplementary material The online version of this article (doi:10.1007/s13258-014-0253-2) contains supplementary material, which is available to authorized users.
    Genes & genomics 01/2015; 37(1):97-109. DOI:10.1007/s13258-014-0253-2 · 0.57 Impact Factor
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    • "Hence, tight regulation of ROS levels in the ovaries is required. The NFE2-related factor 2 (NRF2) pathway is the primary regulator of cellular ROS levels (reviewed in [4] [5] [6] [7]). Under basal conditions, NRF2 protein—encoded by the NFE2L2 gene—is rapidly targeted for proteasomal degradation through interaction with an E3-ubiquitin ligase protein complex, whose protein components include Kelch-like ECH-associated protein 1 (KEAP1), Cullin 3 (CUL3), and ring-box 1, E3-ubiquitin protein ligase (RBX1) (Figure 1). "
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    ABSTRACT: The NFE2-related factor 2 (NRF2) pathway is critical to initiate responses to oxidative stress; however, constitutive activation occurs in different cancer types, including serous ovarian carcinomas (OVCA). The KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex is a regulator of NRF2 levels. Hence, we investigated the DNA-level mechanisms affecting these genes in OVCA. DNA copy-number loss (CNL), promoter hypermethylation, mRNA expression, and sequence mutation for KEAP1, CUL3, and RBX1 were assessed in a cohort of 568 OVCA from The Cancer Genome Atlas. Almost 90% of cases exhibited loss-of-function alterations in any components of the NRF2 inhibitory complex. CNL is the most prominent mechanism of component disruption, with RBX1 being the most frequently disrupted component. These alterations were associated with reduced mRNA expression of complex components, and NRF2 target gene expression was positively enriched in 90% of samples harboring altered complex components. Disruption occurs through a unique DNA-level alteration pattern in OVCA. We conclude that a remarkably high frequency of DNA and mRNA alterations affects components of the KEAP1/CUL3/RBX1 complex, through a unique pattern of genetic mechanisms. Together, these results suggest a key role for the KEAP1/CUL3/RBX1 complex and NRF2 pathway deregulation in OVCA.
    BioMed Research International 07/2014; 2014:159459. DOI:10.1155/2014/159459 · 2.71 Impact Factor
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    • "The latter is due to production of excessive levels of cytotoxic oxidants, including oxygen and nitric oxide free radicals and an imbalance between the production of reactive oxygen species (ROS) and the ability of the anti-oxidant/detoxifying system to prevent and repair the resultant damage [7]. Keap1–Nrf2 [Kelch-likeECH-associated protein 1–nuclear factor (erythroid-derived2)-like2] is the major regulator of cytoprotective responses to oxidative and electrophilic stress that ameliorates traumatic and oxidative stress by coordinating the antioxidant and anti-inflammatory response [8]. Under normal conditions, Nrf2 is present at very low levels in the cellular cytoplasm due to an interaction with Keap1, an ubiquitin ligase adaptor protein that targets Nrf2 for degradation. "
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    ABSTRACT: The Spartathlon race (brisk walking a distance of 246km in less than 36h) was employed as a model of severe physical stress to investigate proteomic alterations in the plasma of athletes at the start (Athens) and finish (Sparta) of the race, as well as 48h after the race (Post). The athletes' plasma was analysed by 2D gel electrophoresis (2-DE) and the differentially expressed proteins were identified by matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry (MS). The ProteoSeek™ Albumin/IgG removal kit and the ProteoMiner™ enrichment kit were utilized to detect medium- and low-abundance proteins, whose expression may be masked due to high-abundance proteins. Our results were confirmed by Western blot and biochemical analyses. Overall fifty-two proteins were differentially expressed between the starting point, the finishing line and two days after the end of the race. Of these, thirty proteins were involved in inflammation, while the rest concerned anti-oxidation, anti-coagulation and iron and vitamin D transport. These results indicate that prolonged physical stress affects circulating stress-related proteins, which might be employed as biomarkers of stress-related diseases. The current study employed the Spartathlon, as a model of prolonged endurance exercise, to identify and isolate putative biomarkers of inflammation under extreme physical stress conditions. These protein quantitative variations may pave the way to exploration and understanding of stress-related physiological processes, the stress response itself and diseases whose onset appears to be linked to stress.
    Journal of proteomics 12/2013; 98. DOI:10.1016/j.jprot.2013.12.004 · 3.93 Impact Factor
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