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Nrf2 Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming
Open accessAbstract
Cancer cells consume large quantities of nutrients and maintain high levels of anabolism. Recent studies revealed that various oncogenic pathways are involved in modulation of metabolism. Nrf2, a key regulator for the maintenance of redox homeostasis, has been shown to contribute to malignant phenotypes of cancers including aggressive proliferation. However, the mechanisms with which Nrf2 accelerates proliferation are not fully understood. Here, we show that Nrf2 redirects glucose and glutamine into anabolic pathways, especially under the sustained activation of PI3K-Akt signaling. The active PI3K-Akt pathway augments the nuclear accumulation of Nrf2 and enables Nrf2 to promote metabolic activities that support cell proliferation in addition to enhancing cytoprotection. The functional expansion of Nrf2 reinforces the metabolic reprogramming triggered by proliferative signals.
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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 [16]
In the citing paper
“The aberrant activation of Nrf2 in cancer cells leads to increased expression of Glucose-6-phosphate dehydrogenase (G6PD), transketolase (TKT), 6-phosphogluconate dehydrogenase (PGD), and other metabolic enzymes promoting glutamine and glucose metabolism in pentose phosphate pathway (PPP) and increasing synthesis of amino acids participating in metabolic reprogramming required for cell prol”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Mitsuishi et al. 2012
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NRF2, a Key Regulator of Antioxidants with Two Faces towards Cancer
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Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition
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InfluentialNrf2 Enhances Cholangiocyte Expansion in Pten-Deficient Livers
Taguchi, K., Hirano, I., Itoh, T., Tanaka, M., Miyajima, A., Suzuki, A., Motohashi, H., & Yamamoto, M. P. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01384-13 · Cited by 98
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Endo, H., Owada, S., Inagaki, Y., Shida, Y., & Tatemichi, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-28074-w · Cited by 97
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Panieri, E., Telkoparan‐Akillilar, P., Süzen, S., & Saso, L. (2020) · Biomolecules · doi:10.3390/biom10050791 · Cited by 102
Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers
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“…antioxidant and detoxification capacities (Wang et al., 2008; Singh et al., 2010), increased proliferation as a result of metabolic reprogramming (Mitsuishi et al., 2012; Singh et al., 2013; DeNicola et al., 2015; Romero et al., 2017), protection of translational machinery from oxidative damage…”
BackgroundSelf-citationThe Pentose Phosphate Pathway in Cancer: Regulation and Therapeutic Opportunities
Ghanem, N., El‐Baba, C., Araji, K., El‐Khoury, R., Usta, J. A., & Darwiche, N. (2021) · Chemotherapy · doi:10.1159/000519784 · Cited by 98
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“The essential effectors mediating the oncogenic role of Nrf2 include detoxification/antioxidant enzymes and enzymes involved in the pentose phosphate pathway and the reduced nicotinamide adenine dinucleotide phosphate production pathway.((35)) Strikingly, in CCA cells depleted of FoxO3, both cytoprotective and anaboli…”
BackgroundDysregulation of NRF2 in Cancer: from Molecular Mechanisms to Therapeutic Opportunities
Jung, B.-J., Yoo, H.-S., Shin, S., Park, Y., & Jeon, S. (2017) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2017.195 · Cited by 104
“Accumulating evidence suggests that the activation of NRF2 is critical for tumor cell proliferation, growth, and survival (Ohta et al., 2008; DeNicola et al., 2011; Mitsuishi et al., 2012; Jia et al., 2016).”
BackgroundGlutamine Metabolism in Brain Tumors
Natarajan, S. K., & Venneti, S. (2019) · Cancers · doi:10.3390/cancers11111628 · Cited by 99
“Interestingly, the PI3K/Akt axis is also shown to drive production of glutathione (GSH) by promoting stability of nuclear factor-like 2 (NRF2, a key regulator of redox homeostasis ) in breast cancers [58,59].”
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“G6PD is regulated by various oncogenes and tumor suppressors including ATM, NRF2, mTORC1, TAp73, and p53 (Cosentino et al., 2011; Du et al., 2013; Duvel et al., 2010; Jiang et al., 2011; Jiang et al., 2013b; Mitsuishi et al., 2012) and is implicated in the pathogenesis of human cancers (Patra and Hay, 2014; Stincone e…”
BackgroundNrf2 deficiency deteriorates diabetic kidney disease in Akita model mice
Liu, Y., Uruno, A., Saito, R., Matsukawa, N., Hishinuma, E., Saigusa, D., Liu, H., & Yamamoto, M. P. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102525 · Cited by 97
“genes G6pdx (encoding glucose-6-phosphate dehydrogenase) and Pgd (encoding 6-phosphogluconate dehydrogenase) [28,67], the glycogen-related gene Gbe1 (encoding glycogen branching enzyme) [25], the gluconeogenesis-related gene G6pc (encoding the”
Self-citationNrf2 Modulation in Breast Cancer
Ghareghomi, S., Habibi-Rezaei, M., Arese, M., Saso, L., & Moosavi‐Movahedi, A. A. (2022) · Biomedicines · doi:10.3390/biomedicines10102668 · Cited by 97
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Bollong, M. J., Yun, H., Sherwood, L., Woods, A. K., Lairson, L. L., & Schultz, P. G. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00448 · Cited by 98
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“…the master transcriptional regulator of the cellular antioxidant response (DeNicola et al., 2011; Ishii et al., 2000; Thimmulappa et al., 2002), and previous work has demonstrated an ability of NRF2 to alter metabolic fluxes (DeNicola et al., 2015; Mitsuishi et al., 2012; Thimmulappa et al., 2006).”
Bricambert, J., Alves‐Guerra, M., Estèves, P., Prip‐Buus, C., Bertrand‐Michel, J., Guillou, H., Chang, C. J., Wal, M. N. V., Canonne‐Hergaux, F., Mathurin, P., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04361-y · Cited by 106
Nuclear Factor Erythroid 2-Related Factor 2 in Regulating Cancer Metabolism
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“Deletion of NRF2 exon 2 (78) miR-144-3p suppresses NRF2 activation (274) Lung NSCLC Hypermethylation of KEAP1 promoter (301) Lung cancer miR-155 promotes malignant transformation (28) p21 disrupts KEAP1-NRF2 connection (111) DPP3 disrupts KEAP1-NRF2 connection (89) CDK20 disrupts KEAP1-NRF2 connection (300) K-RAS prom…”
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“Several signaling pathways, including PI3K (47, 51), ERK (52, 53), and PKC (54), are implicated in increasing Nrf2 expression and its transcriptional activity.”
BackgroundInfluentialDual 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
Roles Nrf2 Plays in Myeloid Cells and Related Disorders
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BackgroundInfluentialThe role of Nrf2 in skeletal muscle contractile and mitochondrial function
Crilly, M. J., Tryon, L. D., Erlich, A. T., & Hood, D. A. (2016) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00042.2016 · Cited by 97
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“When p62 accumulates, it stabilizes NRF2, a key regulator of redox homeostasis that redirects glucose and glutamine into anabolic pathways and supports cancer cell proliferation (42, 44, 51).”
BackgroundNRF2 in Cardiovascular Diseases: a Ray of Hope!
Vashi, R., & Patel, B. M. (2020) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-020-10083-8 · Cited by 95
“NRF2 is also responsible for the regulation of proteasomal protein degradation, cell proliferation, and metabolic reprogramming [35, 40, 41].”
BackgroundThe KEAP1-NRF2 System in Healthy Aging and Longevity
Matsumaru, D., & Motohashi, H. (2021) · Antioxidants · doi:10.3390/antiox10121929 · Cited by 103
Self-citationAerobic glycolysis: a novel target in kidney cancer
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“A recent study by Mitsuishi et al. (132) showed that, in human lung carcinoma A549 cells, Nrf2 modulated metabolic pathways that enhanced cell proliferation in the presence of active PI3K-Akt signaling.”
p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas
Hsieh, M.-H., Choe, J. H., Gadhvi, J. G., Kim, Y. J., Arguez, M. A., Palmer, M., Gerold, H., Nowak, C. M., Do, H., Mazambani, S., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.027 · Cited by 93
“Although recent studies have shown that SCC exhibits heightened cellular anti-oxidative capacity through p63- and NRF2-mediated transcriptional control of genes involved in the PPP, de novo serine biosynthesis, and GSH metabolism (DeNicola et al., 2015; Mitsuishi et al., 2012; Wang et al., 2017), robust glucose influx…”
BackgroundReciprocal Control of the Circadian Clock and Cellular Redox State - a Critical Appraisal
Putker, M., & O'Neill, J. S. (2016) · Molecules and Cells · doi:10.14348/molcells.2016.2323 · Cited by 94
“NRF2 also regulates the expression of several enzymes involved in NADPH production (Mitsuishi et al., 2012), allowing BMAL1:CLOCK-NRF2 regulation of NADP/ NADPH ratio, and therefore antioxidant recycling.”
BackgroundŽdralević, M., Vučetić, M., Daher, B., Marchiq, I., Parks, S. K., & Pouysségur, J. (2017) · Advances in Biological Regulation · doi:10.1016/j.jbior.2017.12.002 · Cited by 93
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Kaufman, J. M., Amann, J. M., Park, K., Arasada, R. R., Li, H., Shyr, Y., & Carbone, D. P. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000173 · Cited by 87
“For instance, NRF2 is a key activator of the oxidative stress response and also plays a role in metabolic reprogramming of cancer cells.(39,40) LKB1-deficient tumors have been shown to be susceptible to oxidative stress, because they are unable to make the appropriate adaptive responses in metabolism and biosynthesis.”
BackgroundCytoprotection “gone astray’’: Nrf2 and its role in cancer
Schäfer, H., Geismann, C., Arlt, A., & Sebens, S. (2014) · OncoTargets and Therapy · doi:10.2147/ott.s36624 · Cited by 93
“cooperates with the PI3K/Akt pathway in the metabolic reprogramming of cancer cells.(66,251,252)”
LKB1 deficiency-induced metabolic reprogramming in tumorigenesis and non-neoplastic diseases
Zhang, Y., Meng, Q., Sun, Q., Xu, Z., Zhou, H., & Wang, Y. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101131 · Cited by 91
“This is consistent with the finding that knockdown of NRF2 decreases the levels of (13)Clabeled GSH in A549 cells with [Ue(13)C5] glutamine medium [62].”
ResultNRF2 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
“…by methylenetetrahydrofolate dehydrogenase, cyclohy-drolase and formyltetrahydrofolate synthetase 1 (MTHFD1) and MTHFD2 appears to be partly and indirectly regulated by NRF2, especially in NRF2-activated cancer cells where NRF2 cooperates with ATF4 (Fan et al., 2014; Mitsuishi et al., 2012).”
InfluentialSelf-citationAn Overview of the Advantages of KEAP1-NRF2 System Activation During Inflammatory Disease Treatment
Keleku-Lukwete, N., Suzuki, M., & Yamamoto, M. P. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7358 · Cited by 90
“…(UGTs), antioxidant enzymes such as glutamate-cysteine ligase (glutathione [GSH] production), HMOX-1 or heme oxygenase-1 (HO-1), thioredoxin reductase-1 (TXNRD1), thioredoxin, and ferritin (48), ABC transporters, and pentose phosphate pathway enzymes expression are induced (9, 29, 51, 52, 75).”
Self-citationBiochemical and cellular basis of oxidative stress: Implications for disease onset
Aramouni, K., Assaf, R., Shaito, A. A., Fardoun, M., Al‐Asmakh, M., Sahebkar, A., & Eid, A. H. (2023) · Journal of Cellular Physiology · doi:10.1002/jcp.31071 · Cited by 97
“Likewise, in human patients, Nrf2 mutations have also been reported, and dysregulation of the Nrf2 pathway contributes to carcinogenesis by inducing aggressive cell proliferation (Mitsuishi et al., 2012; Yamaguchi et al., 2019).”
Nrf2, but not β‐catenin, mutation represents an early event in rat hepatocarcinogenesis
Zavattari, P., Perra, A., Menegon, S., Kowalik, M. A., Petrelli, A., Angioni, M. M., Follenzi, A., Quagliata, L., Ledda‐Columbano, G. M., Terracciano, L., et al. (2015) · Hepatology · doi:10.1002/hep.27790 · Cited by 88
“In this context, it is interesting to note that Nrf2, other than maintaining redox homeostasis in quiescent cells, is able to redirect glucose metabolism into anabolic pathways(30); indeed, while increased Nrf2 expression shifts glucose distribution toward purine nucleotide synthesis (through activation of the pentose…”
BackgroundRare insights into cancer biology
Adam, J., Yang, M., Soga, T., & Pollard, P. J. (2013) · Oncogene · doi:10.1038/onc.2013.222 · Cited by 90
Kelch-like proteins: Physiological functions and relationships with diseases
Shi, X., Xiang, S., Cao, J., Zhu, H., Yang, B., He, Q., & Ying, M. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104404 · Cited by 92
“NRF2 addiction” in lung cancer cells and its impact on cancer therapy
Hammad, A., Namani, A., Elshaer, M., Wang, X. J., & Tang, X. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.09.016 · Cited by 87
The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?
Glorieux, C., Enriquez-Lara, C., González, C. D., Aguirre-Martínez, G. V., & Calderón, P. B. (2024) · Antioxidants · doi:10.3390/antiox13010070 · Cited by 97
“NRF2 plays a role in enhancing glutaminolysis [115], nucleotide metabolism [116], and the upregulation of metabolic enzymes within the pentose phosphate pathway (PPP) [117].”
BackgroundQu, X., Sheng, J., Shen, L., Su, J., Xu, Y., Xie, Q., Yao, W., Zhang, X., & Sun, L. (2017) · PLoS ONE · doi:10.1371/journal.pone.0173712 · Cited by 88
Nrf2 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
“Alternatively, it has also been suggested that Nrf2 may direct reprogramming of intermediary metabolism to support cancer cell growth (12).”
BackgroundOxygen in the tumor microenvironment: effects on dendritic cell function
Paardekooper, L. M., de Vos, W., & van den Bogaart, G. (2019) · Oncotarget · doi:10.18632/oncotarget.26608 · Cited by 89
“H2O2 activates the transcription factor Nrf2 which further upregulates glycolysis-related genes and further contributes to the Warburg effect [2, 3].”
BackgroundCrosstalk between NRF2 and HIPK2 shapes cytoprotective responses
Torrente, L., Sanchez, C., Moreno, R., Chowdhry, S., Cabello, P., Isono, K., Koseki, H., Honda, T., Hayes, J. D., Dinkova‐Kostova, A. T., et al. (2017) · Oncogene · doi:10.1038/onc.2017.221 · Cited by 88
“Although NRF2 is cytoprotective and its transient activation is linked with chemoprevention34, it has become apparent that its sustained activation protects tumour cells against chemo-and radiotherapy and can promote metabolic activities that support cell proliferation and tumour growth35–38.”
Karathedath, S., Rajamani, B. M., Aalam, S. M. M., Abraham, A., Varatharajan, S., Krishnamurthy, P. C., Mathews, V., Velayudhan, S. R., & Balasubramanian, P. (2017) · PLoS ONE · doi:10.1371/journal.pone.0177227 · Cited by 89
Goeman, F., Nicola, F. D., Scalera, S., Sperati, F., Gallo, E., Ciuffreda, L., Pallocca, M., Pizzuti, L., Krasniqi, E., Barchiesi, G., et al. (2019) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2019.07.003 · Cited by 86
“At the same time, NFE2L2 promotes a metabolic reprogramming that sustains cellular proliferation under overactive phosphoinositide 3-kinase–Akt signaling.(27)”
BackgroundCuadrado, A. (2021) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-052220-103416 · Cited by 88
The spatiotemporal regulation of the Keap1–Nrf2 pathway and its importance in cellular bioenergetics
Dinkova‐Kostova, A. T., Baird, L., Holmström, K. M., Meyer, C. J., & Abramov, A. Y. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150003 · Cited by 86
Teng, Y., Zhao, H., Gao, L., Zhang, W., Shull, A. Y., & Shay, C. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-2039 · Cited by 85
“Abundant expression of Nrf2 has been identified in different cancer types including HCC, which may associate with cancer cell proliferation, invasion, and chemoresistance (19,20).”
BackgroundKöhler, U. A., Kurinna, S. M., Schwitter, D., Marti, A. T., Schäfer, M., Hellerbrand, C., Speicher, T., & Werner, S. (2013) · Hepatology · doi:10.1002/hep.26964 · Cited by 85
“Selective Nrf2 regulation under hyperproliferative conditions has also been shown for genes encoding various metabolic enzymes.(32) In the future, it will be interesting to identify the cofactors that modify the response to Nrf2 in a cell-type- and proliferation-dependent manner.”
BackgroundHyperactivity of the transcription factor Nrf2 causes metabolic reprogramming in mouse esophagus
Fu, J., Xiong, Z., Huang, C. D., Li, J., Yang, W., Han, Y., Paiboonrungruan, C., Major, M. B., Chen, K., Kang, X., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.005963 · Cited by 86
“Metabolic pathways such as glycolysis, PPP, glutaminolysis were subject to NRF2 regulation as well (42).”
BackgroundResultZheng, Q., Xing, J., Li, X., Tang, X., & Zhang, D. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103417 · Cited by 87
Merkley, E. D., Metz, T., Smith, R. D., Baynes, J., & Frizzell, N. (2013) · Mass Spectrometry Reviews · doi:10.1002/mas.21382 · Cited by 86
“Nrf2 stabilization has also recently been linked to altered glucose and glutamine metabolism, suggesting that succination of KEAP1 may directly play a role in the metabolic reprogramming that contributes to cancer cell proliferation (Mitsuishi et al., 2012).”
BackgroundXue, M., Momiji, H., Rabbani, N., Barker, G. C., Bretschneider, T., Shmygol, A., Rand, D. A. J., & Thornalley, P. J. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.5962 · Cited by 83
“3F– K); glucose-6-phosphate dehydrogenase and transketolase linked to metabolic re-programming (41) (Fig.”
BackgroundBenito, A., Polat, I. H., Noé, V., Ciudad, C. J., Marín, S., & Cascante, M. (2017) · Oncotarget · doi:10.18632/oncotarget.21601 · Cited by 88
“Its expression and activity have been reported to be regulated by some of the most important oncogenes such as k-ras [11] or p53 [2, 12] and it is one of the core enzymes involved in the response to oxidative stress coordinated by NRF2, a critical transcription factor reported to play a key role in tumorigenesis [9, 1…”
BackgroundInfluentialGlutathione Peroxidase in Health and Diseases
Sarıkaya, E., & Doğan, S. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.91009 · Cited by 83
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
Bono, S., Feligioni, M., & Corbo, M. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00479-8 · Cited by 86
Chen, H., Fu, J., Chen, H., Hu, Y., Soroka, D. N., Prigge, J. R., Schmidt, E. E., Yan, F., Major, M. B., Chen, X. L., et al. (2014) · Chemical Research in Toxicology · doi:10.1021/tx500211x · Cited by 84
Fujii, S., Matsumoto, S., Nojima, S., Morii, E., & Kikuchi, A. (2014) · Oncogene · doi:10.1038/onc.2014.402 · Cited by 83
Gjyshi, O., Bottero, V., Veettil, M. V., Dutta, S., Singh, V. V., Leela, C., & Chandran, B. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004460 · Cited by 84
“Although Nrf2 was dispensable for ROS homeostasis, it was essential for the induction of COX-2, VEGF-A, VEGF-D, Bcl-2, NQO1, GCS, HO1, TKT, TALDO and G6PD gene expression in KSHV-infected HMVEC-d cells.”
BackgroundMethodInfluentialLiu, P., Kerins, M. J., Tian, W., Neupane, D., Zhang, D. D., & Ooi, A. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009591 · Cited by 82
Adaptive redox homeostasis in cutaneous melanoma
Arslanbaeva, L. R., & Santoro, M. M. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101753 · Cited by 87
“Redox homeostasis is regulated by different transcription factors and modulators, generally by nuclear factor erythroid 2-related factor 2 (Nrf2), which controls ROS levels by upregulating antioxidant pathways that produce NADPH and GSH [34].”
BackgroundInfluentialDissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer
DeBlasi, J. M., & DeNicola, G. M. (2020) · Cancers · doi:10.3390/cancers12103023 · Cited by 82
“Furthermore, siRNA depletion of NRF2 in KEAP1 mutant NSCLC cells decreases incorporation of glutamate into GSH [25], suggesting that glutamate production from glutamine could support GSH synthesis.”
BackgroundResultInfluentialRobertson, H., Dinkova‐Kostova, A. T., & Hayes, J. D. (2020) · Cancers · doi:10.3390/cancers12123609 · Cited by 89
“In addition, NRF2-target genes include those encoding enzymes that generate NADPH, such as glucose-6-phosphate dehydrogenase (G6PD), isocitrate dehydrogenase 1 (IDH1), malic enzyme 1 (ME1) and 6-phosphogluconate dehydrogenase (PGD), and so supply reducing equivalents that allow oxidized glutathione and thioredoxin to…”
BackgroundMinj, E., Upadhayay, S., & Mehan, S. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03366-2 · Cited by 82
Moldogazieva, N. T., Zavadskiy, S. P., Astakhov, D. V., & Terentiev, A. A. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.149167 · Cited by 84
BRCA1 And Estrogen/Estrogen Receptor In Breast Cancer: Where They Interact?
Wang, L., & Di, L. (2014) · International Journal of Biological Sciences · doi:10.7150/ijbs.8579 · Cited by 87
“Since PI3K-AKT is able to activate NRF2, it is possible that increased PI3K-AKT compromises the risk of damage brought by the ROS in BRCA1 defect cells, through NRF2 mediated antioxidant pathway [87].”
BackgroundRNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma
Sakurai, T., Isogaya, K., Sakai, S., Morikawa, M., Morishita, Y., Ehata, S., Miyazono, K., & Koinuma, D. (2016) · Oncogene · doi:10.1038/onc.2016.35 · Cited by 82
Cullin 3 Ubiquitin Ligases in Cancer Biology: Functions and Therapeutic Implications
Chen, H., & Chen, R. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00113 · Cited by 85
“Evidence has emerged that the proliferative effect of Keap1–Nrf2 pathway is associated with metabolic reprograming (27).”
Background4-Hydroxynonenal metabolites and adducts in pre-carcinogenic conditions and cancer
Guéraud, F. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.025 · Cited by 86
NRF2 immunolocalization in human breast cancer patients as a prognostic factor
Onodera, Y., Motohashi, H., Takagi, K., Miki, Y., Shibahara, Y., Watanabe, M., Ishida, T., Hirakawa, H., Sasano, H., Yamamoto, M., et al. (2014) · Endocrine-Related Cancer · doi:10.1530/erc-13-0234 · Cited by 81
“0.01) increased compared with that of the control MCF7 cells transiently expressing mutant NRF2 lacking the activation domain (Mitsuishi et al. 2012) (Supplementary Fig.”
BackgroundResultInfluentialSelf-citationDysregulation of Nrf2/Keap1 Redox Pathway in Diabetes Affects Multipotency of Stromal Cells
Rabbani, P. S., Soares, M. A., Hameedi, S. G., Kadle, R. L., Mubasher, A., Kowzun, M. J., & Ceradini, D. J. (2018) · Diabetes · doi:10.2337/db18-0232 · Cited by 82
“To further evaluate the metabolic effects of upregulating Nrf2 levels, we assessed the GSH-to-GSSG ratio, an indicator of cellular redox status that is regulated by Nrf2 targets (19).”
MethodHepatic miR-144 Drives Fumarase Activity Preventing NRF2 Activation During Obesity
Azzimato, V., Chen, P., Barreby, E., Morgantini, C., Levi, L., Vankova, A., Jager, J., Sulen, A., Diotallevi, M., Shen, J. X., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.08.030 · Cited by 81
Rajan, S., Tryphena, K. P., Khan, S. S., Vora, L. K., Srivastava, S., Singh, S. B., & Khatri, D. K. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101915 · Cited by 84
PI3K signaling-regulated metabolic reprogramming: From mechanism to application
Su, W. Y., Tian, L. Y., Guo, L. P., Huang, L., & Gao, W. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188952 · Cited by 88
Rabbani, N., Xue, M., Weickert, M. O., & Thornalley, P. J. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.05.006 · Cited by 82
Targeting Cancer Stem Cell Redox Metabolism to Enhance Therapy Responses
Luo, M., & Wicha, M. S. (2018) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2018.10.003 · Cited by 81
Tkaczenko, H., & Kurhaluk, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031098 · Cited by 80
“Recent studies have explored the effects of metabolic reprogramming on cellular functions in response to various stressors, highlighting its critical role in biological processes and cancer [272,273].”
Cerebrovascular and Neurological Disorders: Protective Role of NRF2
Sivandzade, F., Bhalerao, A., & Cucullo, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143433 · Cited by 79
Metadata
- Authors
- Mitsuishi, Y., Taguchi, K., Kawatani, Y., Shibata, T., Nukiwa, T., Aburatani, H., Yamamoto, M., & Motohashi, H.
- Affiliations
- Tohoku University (JP)
- National Cancer Center Research Institute (JP)
- Research Center for Advanced Science and Technology, The University of Tokyo (JP)
- Corresponding author
- Yamamoto, Masayuki
- Motohashi, Hozumi
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 22
- Issue
- 1
- Pages
- 66-79
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2053047691
- Semantic Scholar
- 280f3f56ddaa915842258eabcbeb792646ef42a7
- Cited by
- 1,395
- References
- 49
- Citations by year
- 2026: 72 · 2025: 85 · 2024: 97 · 2023: 112 · 2022: 132 · 2021: 126 · 2020: 131 · 2019: 108 · 2018: 103 · 2017: 101 · 2016: 89 · 2015: 85 · 2014: 76 · 2013: 63 · 2012: 12
- FWCI
- 30.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23659166, 24249015, 24221011)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Nrf2, tumor metabolic reprogramming, glucose metabolism, glutamine metabolism, anabolic metabolism, PI3K/Akt signaling, cell proliferation, redox homeostasis, cytoprotection
- MeSH terms
- Animals, Cell Division, Glucose, Glutamine, Mice, Transgenic, Neoplasms, Signal Transduction, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, NF-E2-Related Factor 2, Mice
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