The Dual Roles of NRF2 in Cancer

Menegon, Silvia; Columbano, Amedeo; Giordano, Silvia

doi:10.1016/j.molmed.2016.05.002

Cited by 546 publications

(479 citation statements)

References 105 publications

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“…Constitutive activation of the NRF2 pathway and elevated expression of IL-11 are tightly associated with the development of cancer (11,20), IL-11 might contribute, at least in part, to NRF2-dependent oncogenesis in a context-dependent manner. Intriguingly, knockdown of NRF2 could not suppress H 2 O 2 -induced IL11 up-regulation.…”

Section: Discussionmentioning

confidence: 99%

Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production

Nishina

Deguchi

Miura

et al. 2017

Journal of Biological Chemistry

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Edited by Joel GottesfeldNuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that plays a crucial role in protection of cells from electrophile-induced toxicity through up-regulating phase II detoxifying enzymes and phase III transporters. We previously reported that oxidative stress induces up-regulation of interleukin-11 (IL-11), a member of the IL-6 family that ameliorates acetaminophen-induced liver toxicity. However, a role for IL-11 in protection of cells from electrophile-induced toxicity remains unclear. Here we show that an environmental electrophile, 1,2-naphthoquinone (1,2-NQ), but not 15d-prostaglandin J 2 (PGJ 2 ) or tert-butylhydroxyquinone (tBHQ), induced IL-11 production. Consistent with a crucial role for prolonged ERK activation in H 2 O 2 -induced IL-11 production, 1,2-NQ, but not 15d-PGJ 2 or tBHQ, elicited prolonged ERK activation. Conversely, inhibition of the ERK pathway by a MEK inhibitor completely blocked 1,2-NQ-induced IL-11 production at both protein and mRNA levels, further substantiating an intimate cross-talk between ERK activation and 1,2-NQ-induced IL-11 production. Promoter analysis of the Il11 gene revealed that two AP-1 sites were essential for 1,2-NQ-induced promoter activities. Among various members of the AP-1 family, Fra-1 was upregulated by 1,2-NQ, and its up-regulation was blocked by a MEK inhibitor. Although NRF2 was not required for H 2 O 2 -induced IL11 up-regulation, NRF2 was essential for 1,2-NQ-induced IL11 up-regulation by increasing Fra-1 proteins possibly through promoting mRNA translation of FOSL1. Finally, intraperitoneal administration of 1,2-NQ induced body weight loss in wild-type mice, which was further exacerbated in Il11ra1 ؊/؊ mice compared with Il11ra1 ؉/؊ mice. Together, both Fra-1 and NRF2 play crucial roles in IL-11 production that protects cells from 1,2-NQ intestinal toxicity.Electrophiles are electron-deficient compounds that can accept an electron pair to form a covalent bond with its reaction partner (nucleophile), resulting in adducts of macromolecules (e.g. proteins, lipids, and DNA) (1). Such reactive species have been shown to be involved in stress, aging, and cancer through modification of various signaling molecules. It is well recognized that endogenous electrophiles, such as 8-nitro-cGMP, 15-deoxy-prostaglandin J 2 (15d-PGJ 2 ), 3 and nitrated fatty acids, are produced during oxidative stress and inflammation (2, 3) and then activate redox signal transduction pathways associated with up-regulation of antioxidant and anti-inflammation genes (1-3). In addition, there are a variety of electrophiles in the environment (4, 5). For example, particles with an aerodynamic diameter of 2.5 m or less (PM2.5) and tobacco smoke (6) contain an atmospheric electrophile, 1,2-naphtoquinone (1,2-NQ), that activates epidermal growth factor receptor (EGFR) through S-arylation of Cys-121 of protein-tyrosine phosphatase 1B (PTP1B) (7). A transcription factor, NF-E2-related factor 2 (NRF2), is activated and attenuates electrophile-ind...

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Section: Discussionmentioning

confidence: 99%

Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production

Nishina

Deguchi

Miura

et al. 2017

Journal of Biological Chemistry

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“…NRF2 is downstream of the PKR‐like endoplasmic reticulum kinase sensor in the UPR and is one transcription factors that has been shown to regulate ABCC subfamily expression (Chartoumpekis et al ., 2015). NRF2 normally acts like a tumor suppressor, but overactivation of its antioxidant response elements (ARE) activity leads to cell survival of normal and malignant cells (Chartoumpekis et al ., 2015; DeNicola et al ., 2011; Menegon et al ., 2016). It has previously been reported that gemcitabine upregulates the NRF2 pathway, helping to mediate resistance (Avril et al ., 2017; Palam et al ., 2015).…”

Section: Introductionmentioning

confidence: 99%

GRP78‐mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells

et al. 2018

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Chemoresistance is a major therapeutic challenge that plays a role in the poor statistical outcomes in pancreatic cancer. Unfolded protein response (UPR) is one of the homeostasis mechanisms in cancer cells that have been correlated with chemoresistance in a number of cancers including pancreatic cancer. In this study, we show that modulating glucose regulatory protein 78 (GRP78), the master regulator of the UPR, can have a profound effect on multiple pathways that mediate chemoresistance. Our study showed for the first time that silencing GRP78 can diminish efflux activity of ATP‐binding cassette (ABC) transporters, and it can decrease the antioxidant response resulting in an accumulation of reactive oxygen species (ROS). We also show that these effects can be mediated by the activity of specificity protein 1 (SP1), a transcription factor overexpressed in pancreatic cancer. Thus, inhibition of SP1 negatively affects the UPR, deregulates the antioxidant response of NRF2, as well as ABC transporter activity by inhibiting GRP78‐mediated ER homeostasis. Sp1 and NRF2 have been classified as nononcogene addiction genes and thus are imperative to understanding the molecular mechanism of resistance. These finding have huge clinical relevance as both Sp1 and GRP78 are overexpressed in pancreatic cancer patients and increased expression of these proteins is indicative of poor prognosis. Understanding how these proteins may regulate chemoresistance phenotype of this aggressive cancer may pave the way for development of efficacious therapy for this devastating disease.

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“…After translation, Nrf2 is degraded by the proteolytic ubiquitin-proteasome system in the cytoplasm of cells. Kelch-like ECHassociated protein 1 (KEAP1) is a component of the Cullin 3 (CUL3)-based E3 ubiquitin ligase complex and it controls both Nrf2 stability and accumulation [8,9]. Abundant evidence indicates that Nrf2 either functions as a proto-oncogene or supports the transformation other oncogenes [10].…”

Section: Introductionmentioning

confidence: 99%

Quercitrin suppresses hepatocellular carcinoma metastasis and angiogenesis by targeting the Nrf2 signaling pathway

Li¹,

Gao²,

Liu³

et al. 2017

Oncotarget

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The Dual Roles of NRF2 in Cancer

Cited by 546 publications

References 105 publications

Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production

Critical Contribution of Nuclear Factor Erythroid 2-related Factor 2 (NRF2) to Electrophile-induced Interleukin-11 Production

GRP78‐mediated antioxidant response and ABC transporter activity confers chemoresistance to pancreatic cancer cells

Quercitrin suppresses hepatocellular carcinoma metastasis and angiogenesis by targeting the Nrf2 signaling pathway

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