NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer
Open accessAbstract
Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nfe2l2/Nrf2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine epidermal growth factor receptor (EGFR) signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.
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NRF2 steers glucose to anabolic cancer metabolism and prevents oxidation of multiple translational factors to augment protein output.
“For example, NRF2 steers glucose to anabolic cancer metabolism and prevents oxidation of multiple translational factors to augment protein output [15,16].”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [15]
The Introduction and Results report that NRF2 maintains reduced cysteines in multiple translation-related proteins and promotes protein synthesis in pancreatic cancer. The Discussion mentions NRF2-regulated metabolic enzymes and cancer metabolic rewiring, citing Mitsuishi et al., but does not establish the more specific claim that NRF2 steers glucose into anabolic metabolism. (LLM, conf=0.83)
Experimental — accuracy not yet measuredNRF2 is known to augment global protein production by reducing key translation factors such as eEF2.
“Indeed, NRF2 is known to augment global protein production by reducing key translation factors such as eEF2 [15].”
From NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy (2021) · cites this paper as [15]
Nrf2 mediates an antioxidant response program to detoxify ROS, is downstream of several oncogenic drivers, and loss of Nrf2 in this context can impair tumor proliferation.
“For example, the transcription factor Nrf2, which mediates an antioxidant response program to detoxify ROS, is downstream of several oncogenic drivers, and loss of Nrf2 in this context can impair tumor proliferation (Chio et al., 2016; DeNicola et al., 2011).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Chio et al., 2016
Oncogenic KRAS activates the NRF2 antioxidant system by inducing NRF2 expression and constitutively activating NRF2-controlled genes to maintain redox balance and promote tumorigenesis.
“In addition to activating the GOT2/GOT1/Malic Enzyme 1 (ME1) pathway, oncogenic KRAS activates the NRF2 antioxidant system by inducing NRF2 expression59,60 and by constitutively activating the battery of genes controlled by NRF2 to maintain the redox balance and promote tumorigenesis61.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [61]
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“However, ectopic expression of the cysteine to aspartic acid oxidation mimic (Permyakov et al., 2012) of the elongation factor eEF2 led to a significant decrease in the rate of nascent protein synthesis when compared to its wild-type counterpart (Figures 3F and S3L).”
Belalcázar, A. D., Ball, J. G., Frost, L. M., Valentovic, M. A., & Wilkinson, J. (2013) · ISRN Biochemistry · doi:10.1155/2013/637897 · Cited by 37 · cited 2× · see citing works
“This indicates that Nrf2-dependent decrease in [(35)S]-Met incorporation into proteins was not due to alterations in Met to cysteine exchange through the transsulfuration cycle in response to elevated oxidative stress (Belalcázar et al., 2014).”
Self-citationFan, X., Chen, P., Tan, H., Zeng, H., Jiang, Y., Wang, Y., Wang, Y., Hou, X., Bi, H., & Huang, M. (2014) · Drug Metabolism and Disposition · doi:10.1124/dmd.114.059394 · Cited by 37 · cited 1× · see citing works
“This is consistent with earlier reports showing a correlation between the expression of Nrf2 and some of these proteins (Fan et al., 2014; Ke et al., 2013;Malec et al., 2010; Niture and Jaiswal, 2012; Wang et al., 2016). qPCR of polysome fractions revealed an increase in the association of the…”
Translational control and cancer therapy
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“Consistent with reports showing that EGFR signaling is coupled to activation of capdependent translation in EGFR wild-type cells (Patel et al., 2013), EGF supplementation was able to restore defective Akt and Erk activation in KPn organoids (Figure S4N).”
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Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging
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Transcriptional Regulation by Nrf2
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Self-citationRAS Proteins and Their Regulators in Human Disease
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The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
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NRF2 and the Hallmarks of Cancer
Rojo de la Vega, M., Chapman, E., & Zhang, D. D. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.022 · Cited by 1,672 · see citing works
Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer
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“For example, the transcription factor Nrf2, which mediates an antioxidant response program to detoxify ROS, is downstream of several oncogenic drivers, and loss of Nrf2 in this context can impair tumor proliferation (Chio et al., 2016; DeNicola et al., 2011).”
BackgroundFerroptosis in cancer: from molecular mechanisms to therapeutic strategies
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“204 207 However, once oncogenic driver mutations occur, the high expression status of NRF2 in cancer cells may promote tumor progression and therapeutic resistance, 208,209 partly through its ability to defend against ferroptosis.”
BackgroundKeap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis
Romero, R., Sayin, V. I., Davidson, S. M., Bauer, M. R., Singh, S. X., LeBoeuf, S. E., Karakousi, T. R., Ellis, D. C., Bhutkar, A., Sánchez-Rivera, F. J., et al. (2017) · Nature Medicine · doi:10.1038/nm.4407 · Cited by 652 · see citing works
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“changes in global cysteine reactivity [116,117], suggesting that the effects on NRF2 on metabolism may not be limited to direct transcriptional targets.”
BackgroundSelf-citationDixon, S. J., & Stockwell, B. R. (2018) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055844 · Cited by 589 · see citing works
ROS in Cancer: The Burning Question
Chio, I. I. C., & Tuveson, D. A. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.03.004 · Cited by 532 · see citing works
“More recently, oxidizing agents such as buthionine sulfoximine have been shown to functionally inactivate mitogenic signaling cascades driven by AKT in pancreatic ductal cells (Chio et al., 2016) as well as in skeletal muscle cells (Tan et al., 2015).”
BackgroundInfluentialSelf-citationNRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8
Anandhan, A., Dodson, M. B., Shakya, A., Chen, J., Liu, P., Wei, Y., Tan, H., Wang, Q., Jiang, Z., Yang, K. B., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade9585 · Cited by 531 · see citing works
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Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis
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“We recently developed an organoid culture model of PDA, which preserves the unique biological characteristics of normal, PanIN, tumor, and metastatic lesions and allows for direct biochemical comparisons during each stage of disease progression (Boj et al., 2015; Chio et al., 2016).”
Self-citationZhong, Q., Xiao, X., Qiu, Y., Xu, Z., Chen, C., Chong, B., Zhao, X., Hai, S., Li, S., An, Z., et al. (2023) · MedComm · doi:10.1002/mco2.261 · Cited by 442 · see citing works
Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer
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“The Nrf2 transcriptional response is an inducible system activated by redox stress; however, mutant Kras constitutively activates this antioxidant program to suppresses ROS and promote pancreatic tumorigenesis and proliferation (Chio et al., 2016).”
BackgroundMaurya, P. K., Malik, D. S., Yadav, K. K., Kumar, A., Kumar, S., & Kamyab, H. (2019) · Toxicology Reports · doi:10.1016/j.toxrep.2019.05.012 · Cited by 365 · see citing works
The metabolic landscape of RAS-driven cancers from biology to therapy
Mukhopadhyay, S., Vander Heiden, M. G., & McCormick, F. (2021) · Nature Cancer · doi:10.1038/s43018-021-00184-x · Cited by 315 · see citing works
Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling
Luo, M., Li, S., Brooks, M. D., Jiagge, E. M., Zhu, Y., Buschhaus, J. M., Conley, S. J., Fath, M. A., Davis, A., Gheordunescu, E., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.06.006 · Cited by 358 · see citing works
Clinical and Therapeutic Implications of Cancer Stem Cells
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Cell death in pancreatic cancer: from pathogenesis to therapy
Chen, X., Zeh, H. J., Kang, R., Kroemer, G., & Tang, D. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00486-6 · Cited by 339 · see citing works
Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism
Biancur, D. E., Paulo, J. A., Małachowska, B., Quiles Del Rey, M., Sousa, C. M., Wang, X., Sohn, A. S. W., Chu, G. C., Gygi, S. P., Harper, J. W., et al. (2017) · Nature Communications · doi:10.1038/ncomms15965 · Cited by 315 · see citing works
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“of cellular redox, resulting in a reduced intracellular environment (42).”
BackgroundNRF2 as a regulator of cell metabolism and inflammation in cancer
He, F., Antonucci, L., & Karin, M. (2020) · Carcinogenesis · doi:10.1093/carcin/bgaa039 · Cited by 318 · see citing works
“(i) NRF2 stimulates cancer cell proliferation through effects on epidermal growth factor receptor signaling and through upregulation of anabolic metabolism (35,117).”
BackgroundNRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression
Chen, D., Tavana, O., Chu, B., Erber, L. N., Chen, Y., Baer, R. J., & Gu, W. J. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.09.009 · Cited by 321 · see citing works
“…tumor cell proliferation in part by stimulating 224 Molecular Cell 68, 224–232, October 5, 2017 ª 2017 Elsevier Inc NRF2-mediated expression of endogenous antioxidants and reducing reactive oxygen species (ROS) levels (Bauer et al., 2011; Chio et al., 2016; DeNicola et al., 2011; Tao et al., 2014).”
BackgroundTranslational Control in CancerPreprint
Robichaud, N., Sonenberg, N., Ruggero, D., & Schneider, R. J. (2018) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a032896 · Cited by 309 · see citing works
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NRF2 addiction in cancer cells
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Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance
Takahashi, N., Chen, H., Harris, I. S., Stover, D. G., Selfors, L. M., Bronson, R. T., Raedt, T. D., Cichowski, K. M., Welm, A. L., Mori, Y., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.05.001 · Cited by 277 · see citing works
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“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 ini- tiation complex, globally reducing translation (Chio et al. 2016).”
BackgroundChemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer
Bar-Peled, L., Kemper, E. K., Suciu, R. M., Vinogradova, E. V., Backus, K. M., Horning, B. D., Paul, T. A., Ichu, T.-A., Svensson, R. U., Olucha, J., et al. (2017) · Cell · doi:10.1016/j.cell.2017.08.051 · Cited by 262 · see citing works
“A recent cysteine proteomic study performed in Kras-mutated mouse pancreatic cancer organoids deleted for NRF2 expression identified several redox-regulated cysteines (Chio et al., 2016).”
Thirty years of NRF2: advances and therapeutic challenges.
Zhang, D. D. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01145-0 · Cited by 282 · see citing works
“Although not directly involved in the transcription of translation machinery components, NRF2 indirectly promotes mRNA translation by safeguarding the translational machinery from cysteine oxidation, to maintain the functionality of its components 69 .”
Reactive oxygen species and cancer: A complex interaction
Saikolappan, S., Kumar, B., Shishodia, G., Koul, S., & Koul, H. K. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.03.020 · Cited by 249 · see citing works
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“There is also evidence indicating that ROS can diminish the release EGF in pancreatic cancer cells [28].”
BackgroundMETTL13 methylation of eEF1A increases translational output to promote tumorigenesis
Liu, S., Hausmann, S., Carlson, S. M., Fuentes, M. E., Francis, J., Pillai, R., Lofgren, S. M., Hulea, L., Tandoc, K. V., Lu, J.-W., et al. (2019) · Cell · doi:10.1016/j.cell.2018.11.038 · Cited by 175 · see citing works
Fan, J., Ren, D., Wang, J., Liu, X., Zhang, H., Wu, M., & Yang, G. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-2317-3 · Cited by 209 · see citing works
The pleiotropic functions of reactive oxygen species in cancer
Wu, K., Zowalaty, A. E. E., Sayin, V. I., & Papagiannakopoulos, T. Y. (2024) · Nature Cancer · doi:10.1038/s43018-024-00738-9 · Cited by 203 · see citing works
“These studies illustrate the importance of ROS-mediated post-translational modifications, given that a vast number of cysteine and methionine residues can be oxidized across the proteome in a context-dependent manner 98,99 .”
Organoid models of gastrointestinal cancers in basic and translational research
Lau, H. C.-H., Kranenburg, O., Xiao, H., & Yu, J. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0255-2 · Cited by 195 · see citing works
Regulation of Nrf2/ARE Pathway by Dietary Flavonoids: A Friend or Foe for Cancer Management?
Suraweera, T. L., Rupasinghe, H. P. V., Dellaire, G., & Xu, Z. (2020) · Antioxidants · doi:10.3390/antiox9100973 · Cited by 207 · see citing works
“Further, the deficient state of Nrf2 (shNrf2) in SUIT-2 pancreatic cancer cells and murine pancreatic organoids has also been shown to impair epidermal growth factor signaling and translational regulatory proteins, which causes impaired mRNA translation, leading to defects in cell proliferation [195].”
BackgroundInfluentialFeng, R., Morine, Y., Ikemoto, T., Imura, S., Iwahashi, S., Saito, Y., & Shimada, M. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0262-x · Cited by 190 · see citing works
Takahashi, N., Cho, P., Selfors, L. M., Kuiken, H. J., Kaul, R., Fujiwara, T., Harris, I. S., Zhang, T., Gygi, S. P., & Brugge, J. S. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.10.010 · Cited by 186 · see citing works
“In particular, it is controversial whether NRF2 promotes cancer exclusively through maintenance of redox homeostasis based on differences in the extent to which antioxidant treatment rescues NRF2 deficiencyinduced phenotypes (Chio et al., 2016; Denicola et al., 2011; Reddy et al., 2007; Vartanian et al., 2019).”
BackgroundNRF2: KEAPing Tumors Protected
Pillai, R., Hayashi, M., Zavitsanou, A.-M., & Papagiannakopoulos, T. Y. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0922 · Cited by 187 · see citing works
Deubiquitinases Maintain Protein Homeostasis and Survival of Cancer Cells upon Glutathione Depletion
Harris, I. S., Endress, J. E., Coloff, J. L., Selfors, L. M., McBrayer, S. K., Rosenbluth, J. M., Takahashi, N., Dhakal, S., Koduri, V., Oser, M. G., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.020 · Cited by 168 · see citing works
Self-citationKEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
Krall, E. B., Wang, B., Munoz, D. M., Ilic, N., Raghavan, S., Niederst, M. J., Yu, K., Ruddy, D. A., Aguirre, A. J., Kim, J. W., et al. (2017) · eLife · doi:10.7554/elife.18970 · Cited by 160 · see citing works
“Chio et al. recently reported that NRF2 supports pancreatic tumor maintenance, and that combined targeting of AKT and glutathione synthesis inhibits pancreatic cancer (Chio et al., 2016).”
BackgroundNRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer
Weiss‐Sadan, T., Ge, M., Hayashi, M., Gohar, M., Yao, C.-H., de Groot, A., Harry, S. A., Carlin, A. D., Fischer, H., Shi, L., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.01.012 · Cited by 156 · see citing works
The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance
Biancur, D. E., & Kimmelman, A. C. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.04.011 · Cited by 151 · see citing works
The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure
Galiè, M., Covi, V., Tabaracci, G., & Malatesta, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20164009 · Cited by 177 · see citing works
“Also, Nrf2 hyperactivation supports aberrant cell proliferation by both inducing the metabolic switch towards anabolic pathways [148] and modulating mRNA translation [149].”
BackgroundZhang, J., Simpson, C. M., Berner, J., Chong, H. B., Fang, J., Ordulu, Z., Weiss‐Sadan, T., Possemato, A. P., Harry, S. A., Takahashi, M., et al. (2023) · Cell · doi:10.1016/j.cell.2023.04.026 · Cited by 146 · see citing works
Controversy about pharmacological modulation of Nrf2 for cancer therapy
Milković, L., Žarković, N., & Saso, L. (2017) · Redox Biology · doi:10.1016/j.redox.2017.04.013 · Cited by 142 · see citing works
“The loss of Nrf2 led to defected autocrine signaling of epidermal growth factor receptor (EGFR) and to oxidation of specific proteins of translational machinery, which resulted in impaired capdependent and cap-independent mRNA translation [35].”
BackgroundOrganoid based personalized medicine: from bench to bedside
Li, Y., Tang, P., Cai, S., Peng, J., & Hua, G. (2020) · Cell Regeneration · doi:10.1186/s13619-020-00059-z · Cited by 138 · see citing works
Transsulfuration, minor player or crucial for cysteine homeostasis in cancer
Zhang, H., Geltink, R. I. K., Parker, S. J., & Sorensen, P. H. B. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.02.009 · Cited by 137 · see citing works
Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers
Li, L., Wu, Q., Lu, F., Lei, J., Zhou, Y., Liu, Y., Zhu, N., You, Y., Ning, Z., She, T., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1184079 · Cited by 132 · see citing works
Zhao, X., Wang, J., Deng, Y., Liao, L., Zhou, M., Peng, C. Y., & Li, Y. (2021) · Phytotherapy Research · doi:10.1002/ptr.7104 · Cited by 126 · see citing works
“In cancer cells, activation of Nrf2 confers survival and growth advantages (Chio et al., 2016; Rojo de la Vega, Chapman, & Zhang, 2018; Todoric et al., 2017).”
BackgroundPancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells
Pelosi, E., Castelli, G., & Testa, U. (2017) · Biomedicines · doi:10.3390/biomedicines5040065 · Cited by 124 · see citing works
“This transcriptional factor acts by regulating mRNA translation; loss of NRF2 led to defects in autocrine EGFR signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in PDAC cells [96].”
BackgroundXiang, Y., Ye, W., Huang, C., Yu, D., Chen, H., Deng, T., Zhang, F., Lou, B., Zhang, J., Shi, K., et al. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/2360427 · Cited by 123 · see citing works
“Multiple studies suggest that Nrf2 activation possesses a primary position in the growth, metastasis, and apoptosis of pancreatic cancer [6, 7, 9, 11, 12].”
BackgroundMarkers of pancreatic cancer stem cells and their clinical and therapeutic implications
Gzil, A., Zarębska, I., Bursiewicz, W., Antosik, P., Grzanka, D., & Szylberg, Ł. (2019) · Molecular Biology Reports · doi:10.1007/s11033-019-05058-1 · Cited by 121 · see citing works
“One of the gemcitabineinduced effects in affected cancer cells is the production of reactive oxygen species (ROS) [158, 159].”
BackgroundInfluentialMutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells
Lisek, K., Campaner, E., Ciani, Y., Walerych, D., & Sal, G. D. (2018) · Oncotarget · doi:10.18632/oncotarget.24974 · Cited by 118 · see citing works
“While in normal cells the NRF2/Keap1 antioxidant pathway plays a crucial role in maintaining cellular homeostasis and preventing tumorigenesis [1], in cancer cells high expression of NRF2-regulated genes provides them with cytoprotection, contributing to their oncogenic capabilities [8, 9].”
BackgroundThe role of natural products in revealing NRF2 function
Zhang, D. D., & Chapman, E. (2020) · Natural Product Reports · doi:10.1039/c9np00061e · Cited by 120 · see citing works
eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma
Chan, K., Robert, F., Oertlin, C., Kapeller-Libermann, D., Avizonis, D., Gutierrez, J., Handly-Santana, A., Doubrovin, M., Park, J., Schoepfer, C., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13086-5 · Cited by 106 · see citing works
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Class I HDAC inhibitors enhance YB‐1 acetylation and oxidative stress to block sarcoma metastasis
El-Naggar, A. M., Somasekharan, S. P., Wang, Y., Cheng, H., Negri, G. L., Pan, M., Wang, X. Q., Delaidelli, A., Rafn, B., Cran, J., et al. (2019) · EMBO Reports · doi:10.15252/embr.201948375 · Cited by 113 · see citing works
“Moreover, pancreatic carcinoma cells with loss of NRF2 show defects in redox homeostasis and markedly diminished tumor initiation and maintenance, which is linked to translational inhibition due to oxidation of the different members of the translation machinery [17].”
Blasco, M. T., Navas, C., Martín-Serrano, G., Graña-Castro, O., Lechuga, C. G., Martín-Díaz, L., Djurec, M., Li, J., Morales-Cacho, L., Esteban-Burgos, L., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.03.002 · Cited by 115 · see citing works
Keap1‐Nrf2 signaling pathway in angiogenesis and vascular diseases
Guo, Z., & Mo, Z. (2020) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.3053 · Cited by 114 · see citing works
“Nrf2 has been shown to favor the progression as well as chemo- and radio-resistance of several types of cancers, such as lung squamous cell carcinoma and pancreatic cancer (Chio et al., 2016; Jeong et al., 2017; Tsuchida et al., 2017).”
BackgroundTrxR1, Gsr, and oxidative stress determine hepatocellular carcinoma malignancy
McLoughlin, M., Orlicky, D. J., Prigge, J. R., Krishna, P., Talago, E. A., Cavigli, I., Eriksson, S. E., Miller, C. G., Kundert, J. A., Sayin, V. I., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1903244116 · Cited by 110 · see citing works
“Several mouse and human studies have also shown that malignant progression in diverse cancers is favored by chronic activation of Nrf2 (22, 27, 28), and a recent study indicated that Nrf2-deficient mice are resistant to HCC (64).”
BackgroundSelf-citationHe, F., Antonucci, L., Yamachika, S., Zhang, Z., Taniguchi, K., Umemura, A., Hatzivassiliou, G., Roose‐Girma, M., Reina‐Campos, M., Durán, Á., et al. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.01.023 · Cited by 108 · see citing works
Moreira, L., Bakir, B. S., Chatterji, P., Dantes, Z., Reichert, M., & Rustgi, A. K. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.12.004 · Cited by 106 · see citing works
Translational control of aberrant stress responses as a hallmark of cancer
El-Naggar, A. M., & Sorensen, P. H. B. (2018) · The Journal of Pathology · doi:10.1002/path.5030 · Cited by 102 · see citing works
“It was recently shown that loss of NRF2, the master antioxidant response regulator, leads to oxidation of cysteine residues in cysteine-rich translation regulatory proteins in pancreatic cancer cells, resulting in marked attenuation of both cap-dependent and cap-independent translation [69].”
BackgroundWang, X., Li, Y., Li, Z., Lin, S., Wang, H., Sun, J., Lan, C., Wu, L., Sun, D., Huang, C., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-3230 · Cited by 101 · see citing works
Self-citationRuze, R., Song, J., Yin, X., Chen, Y., Xu, R., Wang, C., & Zhao, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01376-w · Cited by 103 · see citing works
“Moreover, as two maintainers of redox homeostasis, the elevated expression of nrf2 and increased intracellular levels of glutathione (GSH) in mice contribute to the initiation and progression of PC.(486) Similarly, while the high generation of ROS caused by the oncogene KRAS increased the proliferation of PC cells and…”
BackgroundThe A to Z of modulated cell patterning by mammalian thioredoxin reductases
Dagnell, M., Schmidt, E. E., & Arnér, E. S. J. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.12.029 · Cited by 100 · see citing works
“Moreover, Nrf2 activation can accelerate malignant cell growth [193] and Nrf2 is indeed typically activated in many tumors [183,194] and is critical for malignant progression of pancreatic, breast, and lung cancers [192,195,196].”
Self-citationSynthetic Lethal Vulnerabilities in <i>KRAS</i>-Mutant Cancers
Aguirre, A. J., & Hahn, W. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031518 · Cited by 90 · see citing works
“Subsequent work has shown that loss of NRF2 impairs autocrine EGFR signaling and leads to oxidation of translational regulatory proteins that inhibit messenger RNA (mRNA) translation and pancreatic cancer cell proliferation (Chio et al. 2016).”
BackgroundCellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics
Frey, N., Venturelli, S., Zender, L., & Bitzer, M. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.146 · Cited by 97 · see citing works
Ma, X., Li, B., Liu, J., Fu, Y., & Luo, Y. (2019) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-019-1053-y · Cited by 97 · see citing works
Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers
Okazaki, K., Anzawa, H., Liu, Z., Ota, N., Kitamura, H., Onodera, Y., Alam, M. M., Matsumaru, D., Suzuki, T., Katsuoka, F., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19593-0 · Cited by 97 · see citing works
Nuclear Factor Erythroid 2-Related Factor 2 in Regulating Cancer Metabolism
Smolková, K., Mikó, E., Kovàcs, T., Leguina‐Ruzzi, A., Sipos, A., & Bai, P. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8024 · Cited by 96 · see citing works
“NRF2 signaling also actively improves cancer survival by maintaining independence of growth factors in K-Ras-associated malignancies; in pancreatic ductal adenocarcinoma (PDAC), NRF2 signaling is upregulated, resulting in improved cancer survival via maintaining phosphorylated levels of EGFR and ERBB2, and by maintain…”
BackgroundColorectal Tumors Require NUAK1 for Protection from Oxidative Stress
Port, J., Muthalagu, N., Raja, M., Ceteci, F., Monteverde, T., Kruspig, B., Hedley, A., Kalna, G., Lilla, S., Neilson, L. J., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0533 · Cited by 94 · see citing works
“With increasing evidence linking elevated NRF2 to aggressive disease (48, 49), disabling antioxidant defenses via transient inhibition of NUAK1 may offer a new strategy for improving therapeutic outcomes in cancer.”
BackgroundDual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review
Qin, J., Cheng, X., Zhang, J., & Zhang, W. (2019) · Cell Communication and Signaling · doi:10.1186/s12964-019-0435-2 · Cited by 94 · see citing works
Oxidative Stress, Nrf2, and Epigenetic Modification Contribute to Anticancer Drug Resistance
Kang, K. A., & Hyun, J. W. (2017) · Toxicological Research · doi:10.5487/tr.2017.33.1.001 · Cited by 92 · see citing works
“Paradoxically, however, recent studies showed that oncogene-induced Nrf2 promotes both ROS detoxification and tumorigenesis (12,15).”
BackgroundNRF2 signalling in cytoprotection and metabolism
Murakami, S., Kusano, Y., Okazaki, K., Akaike, T., & Motohashi, H. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16246 · Cited by 91 · see citing works
“The NRF2-mediated reducing condition is beneficial for maintaining the high efficiency of translation because many ribosomal subunits are susceptible to oxidation of cysteine residues and then subsequent decline in their functionality (Chio et al., 2016).”
Targeting NRF2 to treat cancer
Sivinski, J., Zhang, D. D., & Chapman, E. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.06.003 · Cited by 90 · see citing works
Shaashua, L., Ben-Shmuel, A., Pevsner-Fischer, M., Friedman, G., Levi-Galibov, O., Nandakumar, S., Barki, D., Nevo, R., Brown, L. E., Zhang, W., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34081-3 · Cited by 79 · see citing works
Self-citationNrf2 Mutagenic Activation Drives Hepatocarcinogenesis
Ngo, H. K. C., Kim, D., Cha, Y., Na, H., & Surh, Y. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-3538 · Cited by 88 · see citing works
“Our findings are in agreement with the recently reported observations that activation of Nrf2 promotes the progression lung (38), skin (39), and pancreatic cancers (11,40).”
ResultLi, Q., Zhang, W., Cheng, N., Zhu, Y., Li, H., Zhang, S., Guo, W., & Ge, G. (2023) · Phytomedicine · doi:10.1016/j.phymed.2023.154726 · Cited by 87 · see citing works
Zhou, X., Liu, K., Cui, J., Xiong, J., Wu, H., Peng, T., & Guo, Y. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-01894-x · Cited by 83 · see citing works
CDK20 interacts with KEAP1 to activate NRF2 and promotes radiochemoresistance in lung cancer cells
Wang, Q., Ma, J., Lu, Y., Zhang, S., Huang, J., Chen, J., Bei, J.-X., Yang, K., Wu, G., Huang, K., et al. (2017) · Oncogene · doi:10.1038/onc.2017.161 · Cited by 83 · see citing works
Bioactivation of Napabucasin Triggers Reactive Oxygen Species–Mediated Cancer Cell Death
Froeling, F. E. M., Swamynathan, M. M., Deschênes, A., Chio, I. I. C., Brosnan, E., Yao, M. A., Alagesan, P., Lucito, M. S., Li, J., Chang, A., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-0302 · Cited by 81 · see citing works
Self-citationCrosstalk of intracellular post-translational modifications in cancer
Wu, Z., Huang, R., & Yuan, L. (2019) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2019.108138 · Cited by 81 · see citing works
Targeting reactive oxygen species in development and progression of pancreatic cancer
Durand, N., & Störz, P. (2016) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2017.1261017 · Cited by 78 · see citing works
“In this setting, oxidative damage of key components within the translational regulatory network was inhibited by Nrf2 [59].”
BackgroundInfluentialLiang, C., Shi, S., Liu, M., Qin, Y., Meng, Q., Hua, J., Ji, S., Zhang, Y., Yang, J., Xu, J., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-18-1968 · Cited by 80 · see citing works
“Emerging evidence has demonstrated that Kras, B-Raf, and c-Myc each increase the transcription of NRF2 to elevate the antioxidant program and thereby lower intracellular ROS and confer a further reduced intracellular environment (25, 51).”
BackgroundMethionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis
He, D., Feng, H., Sundberg, B., Yang, J., Powers, J., Christian, A. H., Wilkinson, J. E., Monnin, C., Avizonis, D. Z., Thomas, C. J., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.06.005 · Cited by 77 · see citing works
“To ascertain whether antioxidants can reverse the methionine oxidation status of PKM2 and impede cell migration, we then examined the impact of N-acetylcysteine (NAC), a global antioxidant, or MitoTempo, a mitochondria-targeted superoxide dismutase mimetic, on PDAT-sgMsrA cells.”
BackgroundMethodInfluentialSelf-citationWang, D., Li, Y., Ge, H., Ghadban, T., Reeh, M., & Güngör, C. (2022) · Cancers · doi:10.3390/cancers14163998 · Cited by 77 · see citing works
“NRF2 can be activated by stromal-derived factor 1α (SDF-1α) and IL-6, that are secreted by PSCs [172].”
BackgroundInfluentialBroekgaarden, M., Anbil, S. R., Bulin, A., Obaid, G., Mai, Z., Baglo, Y., Rizvi, I., & Hasan, T. G. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119421 · Cited by 77 · see citing works
The Regulation of NRF2 by Nutrient-Responsive Signaling and Its Role in Anabolic Cancer Metabolism
Lee, S. B., Sellers, B. N., & DeNicola, G. M. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7356 · Cited by 74 · see citing works
“Recently, it was demonstrated that NRF2 promotes the translation of mRNAs by regulating the intracellular redox state (23).”
Self-citationGambardella, V., Gimeno-Valiente, F., Tarazona, N., Martínez‐Ciarpaglini, C., Roda, D., Fleitas, T., Tolosa, P., Cejalvo, J. M., Huerta, M., Roselló, S., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-2421 · Cited by 75 · see citing works
Metastasis in Pancreatic Ductal Adenocarcinoma: Current Standing and Methodologies
Pereira, M. A., & Chio, I. I. C. (2019) · Genes · doi:10.3390/genes11010006 · Cited by 75 · see citing works
“NRF2 has been shown to have a role in PDA initiation [78], tumor maintenance [79] and possibly metastasis [80].”
BackgroundSelf-citationKeap1 mutation renders lung adenocarcinomas dependent on Slc33a1
Romero, R., Rivera, F. J. S., Westcott, P. M. K., Mercer, K. L., Bhutkar, A. J., Muir, A., González-Robles, T. J., Rodríguez, S. L., Liao, L. Z., Ng, S. R., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-0071-1 · Cited by 75 · see citing works
Pillai, R., LeBoeuf, S. E., Hao, Y., New, C., Blum, J. L. E., Rashidfarrokhi, A., Huang, S. M., Bahamon, C., Wu, W., Karadal-Ferrena, B., et al. (2024) · Science Advances · doi:10.1126/sciadv.adm9859 · Cited by 79 · see citing works
Self-citationKEAP1-Mutant NSCLC: The Catastrophic Failure of a Cell-Protecting Hub
Scalera, S., Mazzotta, M., Cortile, C., Krasniqi, E., Maria, R. D., Cappuzzo, F., Ciliberto, G., & Maugeri‐Saccà, M. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.03.011 · Cited by 74 · see citing works
Splicing Factor SRSF1 Promotes Pancreatitis and KRASG12D-Mediated Pancreatic Cancer
Wan, L., Lin, K., Rahman, M. A., Ishigami, Y., Wang, Z., Jensen, M. A., Wilkinson, J. E., Park, Y., Tuveson, D. A., & Krainer, A. R. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-1013 · Cited by 73 · see citing works
“Following immunoprecipitation of cell lysates, immunoprecipitates (IP) and whole-cell extracts (WCE) were analyzed by immunoblotting with the indicated antibodies.”
Self-citation
- Authors
- Chio, I. I. C., Jafarnejad, S. M., Ponz-Sarvise, M., Park, Y., Rivera, K., Palm, W., Wilson, J., Sangar, V., Hao, Y., Öhlund, D., Wright, K., Filippini, D., Lee, E. J., Da Silva, B., Schoepfer, C., Wilkinson, J. E., Buscaglia, J. M., DeNicola, G. M., Tiriac, H., Hammell, M., Crawford, H. C., Schmidt, E. E., Thompson, C. B., Pappin, D. J., Sonenberg, N., & Tuveson, D. A.
- Affiliations
- Cold Spring Harbor Laboratory (US)
- McGill University (CA)
- Memorial Sloan Kettering Cancer Center (US)
- Institute for Systems Biology (US)
- University of Michigan (US)
- Stony Brook School (US)
- Cornell University (US)
- Montana State University (US)
- Corresponding author
- Tuveson, David A.
- ORCID
- Chio, Iok In Christine
- Jafarnejad, Seyed Mehdi
- Park, Youngkyu
- Rivera, Keith
- Palm, Wilhelm
- Öhlund, Daniel
- Filippini, Dea
- Lee, Eun Jung
- Wilkinson, John Erby
- Buscaglia, Jonathan M.
- DeNicola, Gina M.
- Hammell, Molly
- Crawford, Howard C.
- Schmidt, Edward E.
- Thompson, Craig B.
- Pappin, Darryl J.
- Sonenberg, Nahum
- Tuveson, David A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 166
- Issue
- 4
- Pages
- 963-976
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5234705
- OpenAlex
- W2495582206
- Cited by
- 378
- References
- 60
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 31 · 2023: 54 · 2022: 35 · 2021: 54 · 2020: 42 · 2019: 40 · 2018: 43 · 2017: 40 · 2016: 9
- FWCI
- 22.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- eScholarship@McGill (McGill) (submittedVersion, cc-by-nc-nd)
- Funders
- Cancer Center Support (5P30CA045508, P30CA008748)
- CSHL Association
- NIH (5P30CA45508-26, 5P50CA101955-07, 1U10CA180944-01, 5U01CA168409-3, 1R01CA190092-01, AG040020, CA152559, R01 CA159222)
- Carcinoid Foundation
- PCUK
- David Rubinstein Center for Pancreatic Cancer Research at MSKCC
- Stand Up to Cancer
- KWF
- STARR Foundation (I7-A718)
- DOD (W81XWH-13-PRCRP-IA)
- Precision Medicine Research Associates
- Damon Runyon Cancer Research Foundation (DRG-2165-13)
- Human Frontier Science Program (LT000190/2013)
- Cancer Research Society and CCSRI (702317)
- Canadian Institute of Health Research
- Swedish Research Council (537-2013-7277)
- Sociedad Española de Oncología Médica
- Hope Funds for Cancer Research Fellowship
- MSKCC Molecular Cytology Core
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Nrf2, pancreatic cancer, mRNA translation, KRAS, EGFR signaling, autocrine signaling, protein oxidation, cap-dependent translation, cap-independent translation, Akt, synthetic lethality, tumor maintenance
- MeSH terms
- Animals, Cysteine, Glutathione, Humans, Organoids, Pancreatic Neoplasms, Protein Biosynthesis, Signal Transduction, Proto-Oncogene Proteins p21(ras), Autocrine Communication, NF-E2-Related Factor 2, Mice
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