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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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“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]
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“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]
In the citing paper
“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
In the citing paper
“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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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 115
“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
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
“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 111
“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 110
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 112
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 105
“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 105
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 111
“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 101
“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-citationCellular 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
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
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 92
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 101
“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 96
“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
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 94
“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
“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).”
Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers
Aguirre, A. J., & Hahn, W. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031518 · Cited by 90
“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).”
BackgroundTargeting 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 94
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
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 90
“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
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
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
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 82
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
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 79
“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
“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 80
“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 78
“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 78
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 78
“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
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
“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 76
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 81
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 80
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 72
“Following immunoprecipitation of cell lysates, immunoprecipitates (IP) and whole-cell extracts (WCE) were analyzed by immunoblotting with the indicated antibodies.”
Self-citation
Metadata
- 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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