NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

Chio, Iok In Christine; Jafarnejad, Seyed Mehdi; Ponz-Sarvisé, Mariano; Park, Young-Kyu; Rivera, Keith; Palm, Wilhelm; Wilson, John P.; Sangar, Vineet; Hao, Yuan; Öhlund, Daniel; Wright, Kevin; Filippini, Dea; Lee, Eun Jung; Silva, Brandon Da; Schoepfer, Christina; Wilkinson, John E.; Buscaglia, Jonathan M.; DeNicola, Gina M.; Tiriac, Hervé; Hammell, Molly; Crawford, Howard C.; Schmidt, Edward E.; Thompson, Craig B.; Pappin, Darryl; Sonenberg, Nahum; Tuveson, David A.

doi:10.1016/j.cell.2016.06.056

Cited by 302 publications

(252 citation statements)

References 59 publications

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“…Antioxidant treatment of mouse models of lung cancer increases tumor progression and reduces mouse survival by reducing ROS levels, DNA damage, and p53 expression in the cancer cells (Sayin et al 2014). Oxidative stress also impairs cancer progression by globally suppressing protein translation: NRF2-deficient cancer cells show an increase in oxidized cysteine residues in components of the translational initiation complex, globally reducing translation (Chio et al 2016). This phenotype can be rescued by antioxidant treatment.…”

Section: Ros and Metastasismentioning

confidence: 99%

Cancer, Oxidative Stress, and Metastasis

Gill

Piskounova

Morrison

2016

Cold Spring Harb Symp Quant Biol

209

146

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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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Section: Ros and Metastasismentioning

confidence: 99%

Cancer, Oxidative Stress, and Metastasis

Gill

Piskounova

Morrison

2016

Cold Spring Harb Symp Quant Biol

209

146

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“…A recent study has shown that NRF2 promotes mRNA translation of several genes through preventing oxidative stress-dependent blockade of assembly of the translation initiation complex in pancreatic cancer (18). Thus, it is reasonable to hypothesize that NRF2 promotes mRNA translation of FOSL1, thereby increasing protein expression of Fra-1.…”

Section: Discussionmentioning

confidence: 99%

“…6) prompted us to test whether NRF2 might regulate expression of Fra-1 at mRNA or protein levels. Intriguingly, a very recent study has shown that NRF2 promotes mRNA translation of a particular set of genes (18). Although knockdown of NRF2 by siRNA did not affect FOSL1 mRNA expression (Fig.…”

Section: Activation Of the Erk Pathway Is Required For 12-nq-inducedmentioning

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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“…Accordingly, we utilized the organoid model system to determine the mechanism by which Nrf2 maintains PDA proliferation (Chio et al 2016). Knockdown of Nrf2 in human tumor organoids reduced proliferation, whereas knockdown had little effect on normal human organoids.…”

Section: Elucidating the Role Of Nrf2 In Pda Progressionmentioning

confidence: 99%

“…Finally, the combination of Akt inhibiton and BSO treatment was more effective than either drug alone in reducing tumor growth in KPC mice. Therefore, we propose that modulating redox regulation in combination with Akt inhibition should be considered for clinical translation (Chio et al 2016). …”

Section: Elucidating the Role Of Nrf2 In Pda Progressionmentioning

confidence: 99%

Challenges and Opportunities in Modeling Pancreatic Cancer

Feigin

Tuveson

2016

Cold Spring Harb Symp Quant Biol

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The ability to faithfully model complex processes lies at the heart of experimental biology. Although a reductionist approach necessarily reduces this complexity, it is nevertheless required for untangling the contributions and interactions of the various system components. It has long been appreciated that cancer is a complex process that involves positive and negative interactions between tumor cells, normal host tissue, and the associated cells of the tumor microenvironment. However, accurate models for studying these complex interactions in vitro have remained elusive. We seek to generate models of mouse and human pancreatic cancer that are relevant to disease biology and useful for elucidating poorly understood facets of this deadly disease. The ability to model, manipulate, and predict the therapeutic response of an individual's disease outside their body represents the promise of precision medicine. Therefore, these models are patient-specific and allow the identification of new biomarkers and novel treatment modalities for rapid translation to the clinic. In this perspective we will discuss recent advances in modeling pancreatic cancer in vitro, the discoveries these models have enabled, and future challenges and opportunities awaiting further investigation.

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NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

Cited by 302 publications

References 59 publications

Cancer, Oxidative Stress, and Metastasis

Cancer, Oxidative Stress, and Metastasis

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

Challenges and Opportunities in Modeling Pancreatic Cancer

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