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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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Role of nrf2 in oxidative stress and toxicity
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“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
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“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
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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