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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
Citations
Cites
Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B
Cross, D. A. E., Alessi, D. R., Cohen, P., Andjelkovich, M., & Hemmings, B. A. (1995) · Nature · doi:10.1038/378785a0 · Cited by 5,244
Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I., Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., et al. (1997) · Science · doi:10.1126/science.275.5308.1943 · Cited by 4,785
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088
Itoh, K., Chiba, T., Takahashi, S., Ishii, T., Igarashi, K., Katoh, Y., Oyake, T., Hayashi, N., Satoh, K., Hatayama, I., et al. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6943 · Cited by 3,999
DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622
Targeting PI3K signalling in cancer: opportunities, challenges and limitations
Engelman, J. A. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2664 · Cited by 2,445
Tumor cell metabolism: cancer's Achilles' heel
Kroemer, G., & Pouyssegur, J. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.05.005 · Cited by 2,337
Regulation of glutathione synthesis
Lu, S. C.-L. (2008) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2008.05.005 · Cited by 2,131
Activation of a metabolic gene regulatory network downstream of mTOR complex 1
Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.022 · Cited by 2,020
TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis
Bensaad, K., Tsuruta, A., Selak, M. A., Vidal, M. N. C., Nakano, K., Bartrons, R., Gottlieb, E., & Vousden, K. H. (2006) · Cell · doi:10.1016/j.cell.2006.05.036 · Cited by 2,019
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Role of nrf2 in oxidative stress and toxicity
Ma, Q. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140320 · Cited by 4,903
“Nrf2 promotes aggressive proliferation of cancer cells by reinforcing the metabolic programming triggered by proliferative signals; in this scenario, Nrf2 redirects glucose and glutamine into anabolic pathways to support aggressive proliferation (85).”
BackgroundModulation of oxidative stress as an anticancer strategy
Gorrini, C., Harris, I. S., & Mak, T. W. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4002 · Cited by 3,579
Oncogenic Signaling Pathways in The Cancer Genome Atlas
Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.035 · Cited by 3,201
“PI3K pathway activation promotes NRF2 accumulation, which, in turn, mediates metabolic pathways required to sustain cell proliferation and protection from reactive oxidative species (Mitsuishi et al., 2012).”
BackgroundHayes, J. D., Dinkova-Kostova, A. T., & Tew, K. D. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.06.001 · Cited by 2,654
“Studies of Keap1FA/− mice have revealed that constitutive upregulation of Nrf2 increases proliferation of forestomach epithelium, but not cancer (Mitsuishi et al., 2012), and that Nrf2-mediated maximal transactivation of G6pd, Pgd, and Me1 requires activation of the PI3K-Akt signaling pathway, which likely results in…”
BackgroundReactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging
Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2023) · Archives of Toxicology · doi:10.1007/s00204-023-03562-9 · Cited by 2,638
Transcriptional Regulation by Nrf2
Tonelli, C., Chio, I. I. C., & Tuveson, D. A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7342 · Cited by 2,264
“Moreover, Nrf2 has been shown to regulate intermediary metabolism (29, 107).”
BackgroundInfluentialFrom Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119
“BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling
Wang, Y., Branicky, R. S., Noë, A., & Hekimi, S. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201708007 · Cited by 2,274
“ROS stabilize HIF1α and activate NRF2, and their aberrant activation can facilitate adaptations to hypoxia, stimulate angiogenesis, and enhance cell proliferation (Chandel et al., 2000; Semenza, 2003; Mitsuishi et al., 2012).”
The Nrf2 regulatory network provides an interface between redox and intermediary metabolism
Hayes, J. D., & Dinkova‐Kostova, A. T. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.02.002 · Cited by 2,202
Sun, X., Ou, Z., Chen, R., Niu, X., Chen, D., Kang, R., & Tang, D. (2016) · Hepatology · doi:10.1002/hep.28251 · Cited by 2,012
“Interestingly, other studies have indicated that SLC7A11 is a transcriptional target of NRF2.(34,35) Thus, other genes such as SLC7A11 may be involved in the NRF2-mediated protection of ferroptosis, which needs further investigation.”
BackgroundThe KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968
Self-citationThe PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism
Hoxhaj, G., & Manning, B. D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0216-7 · Cited by 2,137
Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
Kobayashi, E. H., Suzuki, T., Funayama, R., Nagashima, T., Hayashi, M., Sekine, H., Tanaka, N., Moriguchi, T., Motohashi, H., Nakayama, K., et al. (2016) · Nature Communications · doi:10.1038/ncomms11624 · Cited by 1,878
Self-citationNRF2, a Transcription Factor for Stress Response and Beyond
He, F., Ru, X., & Wen, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21134777 · Cited by 1,820
“In addition, NRF2 induces expression of genes encoding for transketolase (TKT) and transaldolase 1 (TALDO1), two enzyme for nonoxidative phase of the PPP [35].”
BackgroundMethodInfluentialNRF2 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
Kurutas, E. B. (2015) · Nutrition Journal · doi:10.1186/s12937-016-0186-5 · Cited by 2,152
“Furthermore, increased levels of hydrogen peroxide and increased Nrf2 activity in tumor cells, result in an enhanced anaerobic glycolysis and utilization of the pentose phosphate pathway activity to generate NAD(P)H equivalents necessary for the Trx and GSH-based antioxidative systems [88, 89].”
BackgroundReprogramming of fatty acid metabolism in cancer
Koundouros, N., & Poulogiannis, G. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0650-z · Cited by 1,669
The role of ROS in tumour development and progression
Cheung, E. C., & Vousden, K. H. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-021-00435-0 · Cited by 1,663
The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway
Baird, L., & Yamamoto, M. P. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00099-20 · Cited by 1,648
Self-citationTherapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases
Cuadrado, A., Rojo, A. I., Wells, G., Hayes, J. D., Cousin, S. P., Rumsey, W. L., Attucks, O. C., Franklin, S., Levonen, A., Kensler, T. W., et al. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0008-x · Cited by 1,503
The pentose phosphate pathway and cancer
Patra, K. C., & Hay, N. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.06.005 · Cited by 1,501
The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer
Kansanen, E., Kuosmanen, S. M., Leinonen, H., & Levonen, A.-L. (2013) · Redox Biology · doi:10.1016/j.redox.2012.10.001 · Cited by 1,313
“affects cell proliferation by directing glucose and glutamine towards anabolic pathways augmenting purine synthesis and influencing the pentose phosphate pathway to promote cell proliferation [11] (Fig.”
BackgroundInfluentialThe emerging role of the Nrf2–Keap1 signaling pathway in cancerPreprint
Jaramillo, M. C., & Zhang, D. D. (2013) · Genes & Development · doi:10.1101/gad.225680.113 · Cited by 1,328
“Recently, Mitsuishi et al. (2012) demonstrated that Nrf2 is indeed important for the ability of A549 lung cancer cells to proliferate.”
BackgroundRedox metabolism: ROS as specific molecular regulators of cell signaling and function
Lennicke, C., & Cochemé, H. M. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.08.018 · Cited by 1,308
Phosphorylation of p62 Activates the Keap1-Nrf2 Pathway during Selective Autophagy
Ichimura, Y., Waguri, S., Sou, Y., Kageyama, S., Hasegawa, J., Ishimura, R., Saito, T., Yang, Y., Kouno, T., Fukutomi, T., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.08.003 · Cited by 1,237
“, 2008) and repressed the proliferation of cancer cell lines in which Nrf2 was constitutively activated (Mitsuishi et al., 2012).”
BackgroundSelf-citationDissecting molecular cross-talk between Nrf2 and NF-κB response pathways
Wardyn, J. D., Ponsford, A. H., & Sanderson, C. M. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150014 · Cited by 1,200
Serine and one-carbon metabolism in cancer
Yang, M., & Vousden, K. H. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.81 · Cited by 992
Molecular basis of the Keap1–Nrf2 system
Suzuki, T., & Yamamoto, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.006 · Cited by 995
Self-citationThe emerging role of Nrf2 in mitochondrial function
Dinkova-Kostova, A. T., & Abramov, A. Y. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.04.036 · Cited by 983
“These findings are in close agreement with the much lower (by 50–70%) levels of malate, pyruvate, and succinate that have been observed after a 1-h pulse of [U-(13)C6]glucose in Keap1-KO compared to WT MEF cells [24].”
BackgroundResultNiture, S. K., Khatri, R., & Jaiswal, A. K. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.02.008 · Cited by 873
Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., & Hayes, J. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.021 · Cited by 837
“To a greater or lesser extent, these changes will contribute to drug tolerance, inhibition of inflammatory reactions, increase in cell proliferation, and changes in cell differentiation that are observed when Nrf2 is overexpressed [121, 140, 159, 185].”
InfluentialMitochondrial reactive oxygen species and cancer
Sullivan, L. B., & Chandel, N. S. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-17 · Cited by 826
“Activation of NRF2 increases synthesis of anabolic enzymes and supports tumor growth by increasing production of NADPH increasing and purine biosynthesis [64].”
BackgroundNrf2, the Master Regulator of Anti-Oxidative Responses
Vomund, S., Schäfer, A., Parnham, M., Brüne, B., & Von Knethen, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122772 · Cited by 752
“This is achieved by redirecting glucose and glutamine into anabolic pathways [65].”
BackgroundNRF2 regulates serine biosynthesis in non–small cell lung cancer
DeNicola, G. M., Chen, P.-H., Mullarky, E., Sudderth, J., Hu, Z., Wu, D., Tang, H., Xie, Y., Asara, J. M., Huffman, K. E., et al. (2015) · Nature Genetics · doi:10.1038/ng.3421 · Cited by 768
The Roles of NRF2 in Modulating Cellular Iron Homeostasis
Kerins, M. J., & Ooi, A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7176 · Cited by 755
“For example, NRF2 can upregulate expression of genes in the pentose phosphate pathway, pyruvate cycling (malic enzyme), and folate metabolism (MTHFD2) (100, 165), which can generate cellular NADPH (28, 153).”
BackgroundNrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis
Fan, Z., Wirth, A.-K., Chen, D., Wruck, C. J., Rauh, M., Buchfelder, M., & Savaskan, N. E. (2017) · Oncogenesis · doi:10.1038/oncsis.2017.65 · Cited by 695
Toward clinical application of the Keap1-Nrf2 pathway
Suzuki, T., Motohashi, H., & Yamamoto, M. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.04.005 · Cited by 680
Self-citationThe pentose phosphate pathway in health and disease
TeSlaa, T. A., Ralser, M., Fan, J., & Rabinowitz, J. D. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00863-2 · Cited by 714
Keap1 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
“…relevance of these data derived from GEMM studies for human lung cancer, we performed an integrative analysis using a dataset of human LUAD patient samples (n = 548) from The Cancer Genome Atlas (TCGA) 3 , published Nrf2 datasets 7,19,20 and our GEMM-derived Nrf2-driven transcriptional signature.”
SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans
Blackwell, T. K., Steinbaugh, M. J., Hourihan, J. M., Ewald, C. Y., & Isik, M. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.008 · Cited by 622
“Interestingly, mammalian Nrf2 has been implicated directly in metabolic reprogramming that occurs under conditions of cell proliferation and cancer [3,69,70].”
The double-edged roles of ROS in cancer prevention and therapy
Wang, Y., Qi, H., Liu, Y., Duan, C., Liu, X., Xia, T., Chen, D., Piao, H., & Liu, H. (2021) · Theranostics · doi:10.7150/thno.56747 · Cited by 657
“Furthermore, it has also been demonstrated that NRF2 activation increases the production of NADPH by transcriptionally activating the key enzymes in the PPP and one-carbon metabolism pathways [97, 98].”
BackgroundSivandzade, F., Prasad, S., Bhalerao, A., & Cucullo, L. (2019) · Redox Biology · doi:10.1016/j.redox.2018.11.017 · Cited by 639
The Dual Roles of NRF2 in Cancer
Menegon, S., Columbano, A., & Giordano, S. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.05.002 · Cited by 633
“proliferation by inducing metabolic reprogramming towards anabolic pathways, augmenting purine synthesis, and influencing the pentose phosphate pathway (PPP), a metabolic pathway parallel to glycolysis [19] (Figure 3).”
BackgroundThe Complex Interplay between Antioxidants and ROS in Cancer
Harris, I. S., & DeNicola, G. M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.03.002 · Cited by 659
“NRF2 regulates multiple metabolic pathways at the interface of antioxidant defense and proliferative processes, including the PPP and serine biosynthesis [17,114,115], which may play a dominant role over antioxidant processes at certain stages of tumor progression.”
BackgroundSullivan, M. R., Danai, L. V., Lewis, C. A., Chan, S. H., Gui, D. Y., Kunchok, T., Dennstedt, E. A., Vander Heiden, M. G., & Muir, A. (2019) · eLife · doi:10.7554/elife.44235 · Cited by 588
Singh, A., Venkannagari, S., Oh, K. H., Zhang, Y., Rohde, J. M., Liu, L., Nimmagadda, S., Sudini, K. R., Brimacombe, K. R., Gajghate, S., et al. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00651 · Cited by 626
Nrf2 regulates ROS production by mitochondria and NADPH oxidase
Kovac, S., Angelova, P. R., Holmström, K. M., Zhang, Y., Dinkova‐Kostova, A. T., & Abramov, A. Y. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.11.021 · Cited by 621
Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
Cuadrado, A., Manda, G., Hassan, A., Alcaraz, M. J., Barbas, C., Daiber, A., Ghezzi, P., León, R., López, M. G., Oliva, B., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014753 · Cited by 632
Molecular mechanisms linking exercise to cancer prevention and treatment
Hojman, P., Gehl, J., Christensen, J. F., & Pedersen, B. K. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.09.015 · Cited by 600
“This reprogramming is driven by distinct oncogenic mutations, as seen in the PI3K pathway, or through a more general upregulation of the metabolic machinery with c-Myc mutations (DeBerardinis et al., 2008; Mitsuishi et al., 2012; Tarrado-Castellarnau et al., 2016).”
BackgroundCell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance
Dalleau, S., Baradat, M., Guéraud, F., & Huc, L. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2013.138 · Cited by 580
Targeting immunometabolism as an anti-inflammatory strategy
Pålsson‐McDermott, E. M., & O'Neill, L. A. J. (2020) · Cell Research · doi:10.1038/s41422-020-0291-z · Cited by 590
“Several studies have reported how Nrf2 regulates the pentose phosphate pathway in cancer cells as well as immune cells.(30,31) The microRNAs miR-1 and miR-206 regulate gene expression of key enzymes of the pentose phosphate pathway via Nrf2 and HDAC4.”
BackgroundBACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis
Wiel, C., Le Gal, K., Ibrahim, M. X., Jahangir, C. A., Kashif, M., Yao, H., Ziegler, D. V., Xu, X., Ghosh, T., Mondal, T., et al. (2019) · Cell · doi:10.1016/j.cell.2019.06.005 · Cited by 579
Hydrogen peroxide – production, fate and role in redox signaling of tumor cells
Lennicke, C., Rahn, J., Lichtenfels, R., Wessjohann, L. A., & Seliger, B. (2015) · Cell Communication and Signaling · doi:10.1186/s12964-015-0118-6 · Cited by 593
“In addition, the master regulator of the cellular anti-oxidant response Nrf2 can be activated and stabilized by a number of oncogenes, for example PI3K, K-ras or MYC [47, 113], known to drive signaling cascades that mediate cancer cell proliferation and/or survival.”
BackgroundMethodROS 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
“Furthermore, NRF2 activation has also been shown to promote NADPH production by regulating enzymes in the pentose phosphate and serine biosynthesis pathways in both murine (Wu et al., 2011) and human (DeNicola et al., 2015; Mitsuishi et al., 2012) cells.”
BackgroundInflammaging and Oxidative Stress in Human Diseases: From Molecular Mechanisms to Novel Treatments
Zuo, L., Prather, E. R., Stetskiv, M., Garrison, D. E., Meade, J. R., Peace, T. I., & Zhou, T. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184472 · Cited by 560
“NRF2 can accelerate cancer cell proliferation via direction of anabolic purine synthesis pathways (Table 1) [43].”
BackgroundInfluentialThe KEAP1–NRF2 System in Cancer
Taguchi, K., & Yamamoto, M. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00085 · Cited by 527
“Notably, siRNA-mediated NRF2 knockdown in A549 cells that are addicted to NRF2 significantly decreases the proliferative ability of these cells (26).”
BackgroundInfluentialSelf-citationGenetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527
“Interestingly, NRF2 also modulates the expression of multiple glutamine metabolism genes, including ME1 (Mitsuishi et al. 2012).”
NRF2 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
Modulating NRF2 in Disease: Timing Is Everything
Dodson, M. B., de la Vega, M. R., Cholanians, A. B., Schmidlin, C. J., Chapman, E., & Zhang, D. D. (2018) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021856 · Cited by 540
Autophagy in the liver: functions in health and disease
Ueno, T., & Komatsu, M. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.185 · Cited by 500
Mitochondrial Dysfunction in Cancer
Boland, M. L., Chourasia, A. H., & Macleod, K. F. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00292 · Cited by 521
“NRF2 stabilization promotes metabolic reprograming toward anabolic pathways, such as nucleotide biosynthesis thereby promoting tumor cell growth (307).”
BackgroundTargeting antioxidants for cancer therapy
Glasauer, A., & Chandel, N. S. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.07.017 · Cited by 516
“Hence, cancer cells have the ability to develop resistance to therapeutics that exogenously raise ROS by increasing their antioxidant mechanisms, such as activation and stabilization of the antioxidant master regulator NRF2 [8,11,154] or other ROS scavengers [13,14].”
InfluentialRedox regulation of immunometabolism
Muri, J., & Köpf, M. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-00478-8 · Cited by 519
Rada, P., Rojo, A. I., Evrard‐Todeschi, N., Innamorato, N. G., Cotte, A., Jaworski, T., Tobón-Velasco, J. C., Devijver, H., García‐Mayoral, M. F., LEUVEN, F. V., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00180-12 · Cited by 482
Nrf2 in cancers: A double‐edged sword
Wu, S., Lu, H., & Bai, Y. (2019) · Cancer Medicine · doi:10.1002/cam4.2101 · Cited by 479
Antioxidant response elements: Discovery, classes, regulation and potential applications
Raghunath, A., Sundarraj, K., Raju, N., Arfuso, F., Bian, J., Kumar, A. P., Sethi, G., & Perumal, E. (2018) · Redox Biology · doi:10.1016/j.redox.2018.05.002 · Cited by 483
Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Durán, Á., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.04.006 · Cited by 472
“NRF2 was suggested to induce metabolic reprogramming that favors cell proliferation (DeNicola et al., 2015; Mitsuishi et al., 2012).”
BackgroundHolmström, K. M., Baird, L., Zhang, Y., Hargreaves, I. P., Chalasani, A., Land, J. M., Stanyer, L., Yamamoto, M. P., Dinkova‐Kostova, A. T., & Abramov, A. Y. (2013) · Biology Open · doi:10.1242/bio.20134853 · Cited by 459
“…and three of the enzymes of the pentose phosphate pathway (namely, glucose-6-phosphate dehydrogenase, transaldolase, and transketolase), is severely decreased in the absence of Nrf2 (Lee et al., 2003a; Lee et al., 2003b; Mitsuishi et al., 2012; Thimmulappa et al., 2002; Wu et al., 2011).”
BackgroundInfluentialSelf-citationThe complexity of the Nrf2 pathway: beyond the antioxidant response
Huang, Y. S., Li, W., Su, Z., & Kong, A. T. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.08.001 · Cited by 459
“NADPH through anabolic pathways [206].”
Metabolic Regulation by p53 Family Members
Berkers, C. R., Maddocks, O. D. K., Cheung, E. C., Mor, I., & Vousden, K. H. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.06.019 · Cited by 458
Functions of autophagy in normal and diseased liver
Czaja, M. J., Ding, W., Donohue, T. M., Friedman, S. L., Js, K., Komatsu, M., Lemasters, J. J., Lemoine, A., Lin, J. D., Ou, J. J., et al. (2013) · Autophagy · doi:10.4161/auto.25063 · Cited by 439
Redox regulation by NRF2 in aging and disease
Schmidlin, C. J., Dodson, M. B., Madhavan, L., & Zhang, D. D. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.01.016 · Cited by 450
“NRF2 target genes are important enzymes in a variety of metabolic pathways including the pentose phosphate pathway (glucose-6-phosphastedehydrogenase [G6PD], phosphogluconate dehydrogenase [PGD]) and purine biosynthesis (bifunctional methylenetetrahydrofolate dehydrogenase [MTHFD2]) [32, 33].”
BackgroundNrf2–MafG heterodimers contribute globally to antioxidant and metabolic networks
Hirotsu, Y., Katsuoka, F., Funayama, R., Nagashima, T., Nishida, Y., Nakayama, K., Engel, J. D., & Yamamoto, M. P. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks827 · Cited by 431
Self-citationOncometabolites: linking altered metabolism with cancer
Yang, M. H., Soga, T., & Pollard, P. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67228 · Cited by 441
“Several lines of evidence suggest that activation of the NRF2-mediated antioxidant defense pathway may promote tumorigenesis by enhanced ROS detoxification as well as conferring a more reduced intracellular environment that can promote cell survival and proliferation (66, 67).”
The Role of Reactive Oxygen Species in Arsenic Toxicity
Hu, Y., Li, J., Lou, B., Wu, R., Wang, G., Lu, C., Wang, H., Pi, J., & Xu, Y. (2020) · Biomolecules · doi:10.3390/biom10020240 · Cited by 426
Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer
Koundouros, N., & Poulogiannis, G. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00160 · Cited by 425
“org May 2018 | Volume 8 | Article 160 glycolysis to the PPP activated by Nrf2, thus maintaining a stable pool of NADPH, which could be used for anabolic processes to sustain tumor growth and proliferation, or ROS detoxification (77, 78) (Figure 2).”
BackgroundThe Role of the Pentose Phosphate Pathway in Diabetes and Cancer
Ge, T., Yang, J., Zhou, S., Wang, Y., Li, Y., & Tong, X. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00365 · Cited by 428
“When the PI3K/Akt signaling pathway is activated, NRF2 directly increases G6PD, 6PGD, TKT, and TALDO expression to enhance metabolic activities and promote cancer cell growth (58).”
BackgroundRoles of Autophagy in Oxidative Stress
Yun, H. R., Jo, Y. H., Kim, J., Shin, Y., Kim, S. S., & Choi, T. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093289 · Cited by 410
Suzuki, T., & Yamamoto, M. P. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.800169 · Cited by 412
Self-citationMitochondria as biosynthetic factories for cancer proliferation
Ahn, C. S., & Metallo, C. M. (2015) · Cancer & Metabolism · doi:10.1186/s40170-015-0128-2 · Cited by 399
“Not surprisingly, activation of cellular antioxidant response pathways is commonly observed in cancer or subpopulations of cells within tumors [46,78].”
BackgroundDeshmukh, P. H., Unni, S., Krishnappa, G., & Padmanabhan, B. (2016) · Biophysical Reviews · doi:10.1007/s12551-016-0244-4 · Cited by 405
“These proteins are responsible for purines synthesis, which are the building blocks of DNA and RNA, which in turn, leads to the proliferation of cancer cells (Mitsuishi et al. 2012).”
BackgroundInfluentialEmploying Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer
Halbrook, C. J., & Lyssiotis, C. A. (2017) · Cancer Cell · doi:10.1016/j.ccell.2016.12.006 · Cited by 403
The Keap1–Nrf2 system in cancers: stress response and anabolic metabolism
Mitsuishi, Y., Motohashi, H., & Yamamoto, M. P. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00200 · Cited by 411
“Then, what is the role of Nrf2 in promoting cell proliferation in the absence of external insults? We recently found that Nrf2 redirects glucose and glutamine into anabolic pathways and promotes metabolic activities that are advantageous for proliferation (Mitsuishi et al., 2012).”
BackgroundInfluentialSelf-citationNRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer
Chio, I. I. C., Jafarnejad, S. M., Ponz-Sarvise, M., Park, Y., Rivera, K., Palm, W., Wilson, J., Sangar, V., Hao, Y., Öhlund, D., et al. (2016) · Cell · doi:10.1016/j.cell.2016.06.056 · Cited by 378
“Hif1a likely contributes to the glycolytic phenotype of PDA (Ying et al., 2012), working in parallel with NRF2 transcriptional target genes that are metabolic enzymes governing the pentose phosphate pathway (Mitsuishi et al., 2012) to promote metabolic rewiring in cancer cells.”
Kuehne, A., Emmert, H., Soehle, J., Winnefeld, M., Fischer, F. F., Wenck, H., Gallinat, S., Terstegen, L., Lucius, R., Hildebrand, J., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.06.017 · Cited by 389
Understanding metabolic regulation and its influence on cell physiology
Metallo, C. M., & Vander Heiden, M. G. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.018 · Cited by 367
“Multiple Regulatory Events Converge on the Oxidative Pentose Phosphate Pathway The oxidative pentose phosphate pathway (PPP; red arrows) generates NADPH to maintain reduced glutathione, combat reactive oxygen species (ROS), and maintain redox homeostasis.”
BackgroundInfluentialThe multifaceted role of Nrf2 in mitochondrial function
Holmström, K. M., Kostov, R. V., & Dinkova-Kostova, A. T. (2016) · Current Opinion in Toxicology · doi:10.1016/j.cotox.2016.10.002 · Cited by 368
Saito, T., Ichimura, Y., Taguchi, K., Suzuki, T., Mizushima, T., Takagi, K., Hirose, Y., Nagahashi, M., Iso, T., Fukutomi, T., et al. (2016) · Nature Communications · doi:10.1038/ncomms12030 · Cited by 372
“Purified Keap1 (1 mM) was pre-treated with or without the indicated compounds in pull-down assay buffer (20mM Tris-HCl (pH 7.5), 150mM NaCl, 0.5% NP-40, 0.5mM TCEP), and then 6 His-GST-Neh2(1-56) (1 mM) or 6 His-GST-Neh2(D17-51) (1 mM) was added to the mixture.”
BackgroundMethodInfluentialSelf-citationEnvironmental pollutants and the immune response
Suzuki, T., Hidaka, T., Kumagai, Y., & Yamamoto, M. P. (2020) · Nature Immunology · doi:10.1038/s41590-020-0802-6 · Cited by 373
Self-citationThe role of Nrf2 signaling in counteracting neurodegenerative diseases
Dinkova‐Kostova, A. T., Kostov, R. V., & Kazantsev, A. G. (2018) · The FEBS Journal · doi:10.1111/febs.14379 · Cited by 342
An essential role for functional lysosomes in ferroptosis of cancer cells
Torii, S., Shintoku, R., Kubota, C., Yaegashi, M., Torii, R., Sasaki, M., Suzuki, T., Mori, M., Yoshimoto, Y., Takeuchi, T., et al. (2016) · Biochemical Journal · doi:10.1042/bj20150658 · Cited by 349
Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease
Irazabal, M. V., & Torres, V. E. (2020) · Cells · doi:10.3390/cells9061342 · Cited by 359
“Interestingly, the activation of the Nrf2-mediated antioxidant response confers a more reduced intracellular environment through the process of ROS detoxification [99,100].”
BackgroundA metabolite-derived protein modification integrates glycolysis with KEAP1–NRF2 signalling
Bollong, M. J., Lee, G., Coukos, J. S., Yun, H., Zambaldo, C., Chang, J. W., Chin, E. N., Ahmad, I., Chatterjee, A. K., Lairson, L. L., et al. (2018) · Nature · doi:10.1038/s41586-018-0622-0 · Cited by 344
Ferroptosis in health and disease
Berndt, C., Alborzinia, H., Skafar, V., Ayton, S., Barayeu, U., Bartelt, A., Bayır, H., Bebber, C. M., Birsoy, K., Böttcher, J. P., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103211 · Cited by 372
Self-citationThe Role of PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma Metabolism
Tian, L., Smit, D. J., & Jücker, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032652 · Cited by 355
“Activation of the PI3K/AKT signaling pathway leads to higher G6PD activity, thereby enhancing metabolic activities and promoting cancer cell growth [51].”
BackgroundInfluentialTranscription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis
Singh, A., Happel, C., Manna, S. K., Acquaah-Mensah, G., Carrerero, J., Kumar, S., Nasipuri, P., Krausz, K. W., Wakabayashi, N., Dewi, R., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66353 · Cited by 333
“We conclude, therefore, that an NRF2-mediated metabolic shift provides cancer cells with building blocks for RNA and DNA synthesis, as well as NADPH, all of which are necessary to maintain a high rate of proliferation (1, 3, 46, 47).”
The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus
Uruno, A., Furusawa, Y., Yagishita, Y., Fukutomi, T., Muramatsu, H., Negishi, T., Sugawara, A., Kensler, T. W., & Yamamoto, M. P. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00225-13 · Cited by 339
“In addition, Nrf2 is involved in glucose regulation in cancer cells (16).”
BackgroundSelf-citationCancer stem cell in breast cancer therapeutic resistance
Bai, X., Ni, J., Beretov, J., Graham, P., & Li, Y. (2018) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2018.07.004 · Cited by 336
Mukhopadhyay, S., Goswami, D., Adiseshaiah, P. P., Burgan, W., Yi, M., Guerin, T. M., Kozlov, S. V., Nissley, D. V., & McCormick, F. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-1363 · Cited by 279
“NRF2 regulates the expression of a battery of cytoprotective genes, including those involved in drug detoxification and redox balance (17, 18), and it plays a critical role in anabolic cancer metabolism by altering glucose and glutamine metabolism (19).”
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 329
“Genes encoding enzymes of the one carbon metabolism, such as MTHFD2, are also activated by NRF2.”
BackgroundInfluential
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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