Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth

Ohta, Tsutomu; Iijima, Kazuhiko; Miyamoto, Mamiko; Nakahara, Izumi; Tanaka, Hiroshi; Ohtsuji, Makiko; Suzuki, Takafumi; Kobayashi, Akira; Yokota, Jun; Sakiyama, Takaharu; Shibata, Tatsuhiro; Yamamoto, Masayuki; Hirohashi, Setsuo

doi:10.1158/0008-5472.can-07-5003

Cited by 570 publications

(506 citation statements)

References 22 publications

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“…This observation implicates aberrant Nrf2 activation in the process of human cancer development. In this regard, recent studies have revealed genetic alterations in KEAP1 that can lead to uncontrolled Nrf2 activation in cancers of the lung (14)(15)(16). Although polymorphisms have been identified in the promoter region of the Nrf2 gene (17,18), which are thought to predispose individuals to lung injury and oxidative related diseases, no conclusive findings on the occurrence of genetic variations in the coding region have yet been published.…”

mentioning

confidence: 99%

Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy

Shibata

Ohta²,

Tong

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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659

642

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The nuclear factor E2-related factor 2 (Nrf2) is a master transcriptional activator of genes encoding numerous cytoprotective enzymes that are induced in response to environmental and endogenously derived oxidative/electrophilic agents. Under normal, nonstressed circumstances, low cellular concentrations of Nrf2 are maintained by proteasomal degradation through a Keap1-Cul3-Roc1-dependent mechanism. A model for Nrf2 activation has been proposed in which two amino-terminal motifs, DLG and ETGE, promote efficient ubiquitination and rapid turnover; known as the two-site substrate recognition/hinge and latch model. Here, we show that in human cancer, somatic mutations occur in the coding region of NRF2, especially among patients with a history of smoking or suffering from squamous cell carcinoma; in the latter case, this leads to poor prognosis. These mutations specifically alter amino acids in the DLG or ETGE motifs, resulting in aberrant cellular accumulation of Nrf2. Mutant Nrf2 cells display constitutive induction of cytoprotective enzymes and drug efflux pumps, which are insensitive to Keap1-mediated regulation. Suppression of Nrf2 protein levels by siRNA knockdown sensitized cancer cells to oxidative stress and chemotherapeutic reagents. Our results strongly support the contention that constitutive Nrf2 activation affords cancer cells with undue protection from their inherently stressed microenvironment and anti-cancer treatments. Hence, inactivation of the Nrf2 pathway may represent a therapeutic strategy to reinforce current treatments for malignancy. Congruously, the present study also provides in vivo validation of the two-site substrate recognition model for Nrf2 activation by the Keap1-Cul3-based E3 ligase.cancer cell microenvironment ͉ multidrug resistant-associated protein ͉ oxidative stress ͉ somatic mutation ͉ ubiquitin-proteasome system

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mentioning

confidence: 99%

Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy

Shibata

Ohta²,

Tong

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

659

642

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“…This phenotype can be rescued by antioxidant treatment. Consistent with the critical role of NRF2 in redox regulation, some cancers suppress ROS by mutations in KEAP1 or NRF2 that prevent NRF2 from being sequestered in the cytoplasm, constitutively activating NRF2 (Singh et al 2006;Ohta et al 2008;Shibata et al 2008a,b).…”

Section: Ros and Metastasismentioning

confidence: 85%

Cancer, Oxidative Stress, and Metastasis

Gill

Piskounova

Morrison

2016

Cold Spring Harb Symp Quant Biol

231

164

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Reactive oxygen species (ROS) are highly reactive molecules that arise from a number of cellular sources, including oxidative metabolism in mitochondria. At low levels they can be advantageous to cells, activating signaling pathways that promote proliferation or survival. At higher levels, ROS can damage or kill cells by oxidizing proteins, lipids, and nucleic acids. It was hypothesized that antioxidants might benefit high-risk patients by reducing the rate of ROS-induced mutations and delaying cancer initiation. However, dietary supplementation with antioxidants has generally proven ineffective or detrimental in clinical trials. High ROS levels limit cancer cell survival during certain windows of cancer initiation and progression. During these periods, dietary supplementation with antioxidants may promote cancer cell survival and cancer progression. This raises the possibility that rather than treating cancer patients with antioxidants, they should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance.

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“…Importantly, NRF2 activation and KEAP1 inactivation mutations leading to permanent constitutive adaptive activation of the NRF2 pathway are increasingly observed in cancers [8,9,10] and other diseases [11,12]. It is well known that several therapeutic strategies, for example anticancer radiotherapy and chemotherapy, largely depend on ROS manipulation to induce cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Khalil¹,

Deeni²

2015

Biodiscovery

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of the antioxidant response (AR) pathway and functions as a transcription factor for basal and oxidative stress-induced expression of a battery of detoxification enzymes and cytoprotective genes. Recent evidence has also demonstrated a role of NRF2 in driving resistance of numerous cancers to chemotherapeutic agents. ATM and ATR are serine/threonine kinases that are activated following DNA damage and function as central components of DNA Damage Response (DDR) pathway. Activities of these kinases cause cell cycle arrest and activate DNA repair signals leading to cytoprotection against genotoxic agents. In this study, we elucidated the roles of ATM-and ATR-dependent DDR and NRF2-mediated AR pathways in promoting cytoprotection following cisplatin challenge in ovarian cancer cell line models. We also determined whether these pathways were inter-dependent for full activation following genotoxic insults and as such demonstrated crosstalk in their signaling mechanism to elicit cytoprotective pathways. Treatment with cisplatin caused NRF2 induction and generation of reactive oxygen species (ROS) that caused cytotoxicity in ovarian cancer cells. This was attenuated by the ROS scavenger N-Acetyl cysteine, implicating NRF2 function in cytoprotection against cisplatin. Treatment with retinoic acid (RA) caused down regulation of NRF2, disruption of AR pathway, significant accumulation of ROS and enhanced cisplatin cytotoxicity. Interestingly, RA treatment also led to repression of total ATM and ATR proteins and aberrant DDR activation following cisplatin challenge. In order to determine whether the RA induced ATM and ATR repression was dependent on NRF2 inhibition, we silenced NRF2 using SiRNA. This caused transcriptional repression of both ATM and ATR expression as determined by their promoter driven luciferase assays. Thus, NRF2 inhibition led to DDR suppression by down-regulating ATM and ATR that led to enhanced cytotoxicity. These findings demonstrate mechanism of crosstalk between the AR and the DDR pathways and extend the scope of NRF2 in promoting cancer therapeutic resistance.

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Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth

Cited by 570 publications

References 22 publications

Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy

Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy

Cancer, Oxidative Stress, and Metastasis

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

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