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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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 [16]
Aberrant activation of Nrf2 in cancer cells leads to increased expression of G6PD, TKT, PGD, and other metabolic enzymes promoting glutamine and glucose metabolism in PPP and increasing synthesis of amino acids participating in metabolic reprogramming required for cell proliferation.
“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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“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 · see citing works
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 · see citing works
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 690 · see citing works
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 · see citing works
“…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 · see citing works
“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 646 · see citing works
“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 · see citing works
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 · see citing works
“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 638 · see citing works
“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 · see citing works
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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 607 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
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 579 · see citing works
“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 · see citing works
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 572 · see citing works
“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 · see citing works
“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 545 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
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 · see citing works
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 502 · see citing works
“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 502 · see citing works
“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 501 · see citing works
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 474 · see citing works
Nrf2 in cancers: A double‐edged sword
Wu, S., Lu, H., & Bai, Y. (2019) · Cancer Medicine · doi:10.1002/cam4.2101 · Cited by 473 · see citing works
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 470 · see citing works
Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Duran, A., et al. (2016) · Cancer Cell · doi:10.1016/j.ccell.2016.04.006 · Cited by 438 · see citing works
“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 451 · see citing works
“…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 449 · see citing works
“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 443 · see citing works
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 435 · see citing works
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 441 · see citing works
“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 · see citing works
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 424 · see citing works
“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 · see citing works
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 420 · see citing works
“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 413 · see citing works
“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 403 · see citing works
Suzuki, T., & Yamamoto, M. P. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.800169 · Cited by 402 · see citing works
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 · see citing works
“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 397 · see citing works
“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 394 · see citing works
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 394 · see citing works
“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 · see citing works
“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 380 · see citing works
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 · see citing works
“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 · see citing works
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 364 · see citing works
“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 361 · see citing works
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 · see citing works
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 · see citing works
Reactive Oxygen Species and Redox Signaling in Chronic Kidney Disease
Irazabal, M. V., & Torres, V. E. (2020) · Cells · doi:10.3390/cells9061342 · Cited by 354 · see citing works
“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 · see citing works
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 354 · see citing works
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 345 · see citing works
“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 · see citing works
“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 330 · see citing works
“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 328 · see citing works
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 · see citing works
“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 318 · see citing works
“Genes encoding enzymes of the one carbon metabolism, such as MTHFD2, are also activated by NRF2.”
BackgroundInfluential
- 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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