Cited by 57Genomics, phytochemicals, and oxidative stressCancer, Hypoxia, and MetabolismSulfur Compounds in Biology

Metabolic features of cancer cells in NRF2 addiction status

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Okazaki, Keito, Papagiannakopoulos, Thales, Motohashi, Hozumi·2020·Biophysical Reviews

Abstract

The KEAP1-NRF2 system is a sulfur-employing defense mechanism against oxidative and electrophilic stress. NRF2 is a potent transcription activator for genes mediating sulfur-involving redox reactions, and KEAP1 controls the NRF2 activity in response to the stimuli by utilizing reactivity of sulfur atoms. In many human cancer cells, the KEAP1-mediated regulation of NRF2 activity is abrogated, resulting in the persistent activation of NRF2. Persistently activated NRF2 drives malignant progression of cancers by increasing therapeutic resistance and promoting aggressive tumorigenesis, a state termed as NRF2 addiction. In NRF2-addicted cancer cell, NRF2 contributes to metabolic reprogramming in cooperation with other oncogenic pathways. In particular, NRF2 strongly activates cystine uptake coupled with glutamate excretion and glutathione synthesis, which increases consumption of intracellular glutamate. Decreased availability of glutamate limits anaplerosis of the TCA cycle, resulting in low mitochondrial respiration, and nitrogen source, resulting in the high dependency on exogenous non-essential amino acids. The highly enhanced glutathione synthesis is also likely to alter sulfur metabolism, which can contribute to the maintenance of the mitochondrial membrane potential in normal cells. The potent antioxidant and detoxification capacity supported by abundant production of glutathione is achieved at the expense of central carbon metabolism and requires skewed metabolic flow of sulfur. These metabolic features of NRF2 addiction status provide clues for novel therapeutic strategies to target NRF2-addicted cancer cells.

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  • Cells in several types of cancers are characterized by significant enhancement of glutathione biosynthesis, and this metabolic vulnerability has been targeted to sensitize these cancer cells to ROS-induced drugs.

    “Furthermore, cells in several types of cancers are characterized by significant enhancement of glutathione biosynthesis, and this metabolic vulnerability has been targeted to sensitize these cancer cells to ROS-induced drugs63.”

    From Glutamine reliance in cell metabolism (2020) · cites this paper as [63]

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Authors
Okazaki, K., Papagiannakopoulos, T., & Motohashi, H.
Affiliations
  • Tohoku University (JP)
  • New York University (US)
Corresponding author
Motohashi, Hozumi
Venue
Biophysical Reviews
Published
2020-02-28
Volume
12
Issue
2
Pages
435-441
ISSN
  • 1867-2450 (ISSN-L)
  • 1867-2469
OpenAlex
W3008733464
Cited by
57
References
44
Citations by year
2026: 5 · 2025: 9 · 2024: 6 · 2023: 10 · 2022: 13 · 2021: 7 · 2020: 7
FWCI
0.89
Type
journal article
Language
en
Open access
Locations
  • Biophysical Reviews (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1K22 CA201088-01, 1R37CA222504-01A1, 1R01CA227649-01)
  • American Cancer Society (RSG-17-200-01)
  • Japan Society for the Promotion of Science (18H02621, 18H04794)
  • Naito Foundation (-)
  • Princess Takamatsu Cancer Research Fund (15-24728)
  • Uehara Memorial Foundation (-)
  • Japan Agency for Medical Research and Development (JP19gm5010002)
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 › Biochemistry › Sulfur Compounds in Biology
Keywords
cancer metabolism, metabolic reprogramming, cystine uptake, glutathione synthesis, TCA cycle anaplerosis, mitochondrial respiration, sulfur metabolism, oxidative stress, electrophilic stress, treatment resistance

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