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Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

Janine M DeBlasi1,2, Gina M DeNicola1

  • 1Department of Cancer Physiology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.

Cancers
|October 21, 2020
PubMed

Insights

The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2) regulates cellular responses to stress and metabolism. This review explores how NRF2 and its regulator KEAP1 (Kelch-like ECH-associated protein 1) interact with metabolic pathways.

Area of Science:

  • Cellular Biology
  • Metabolism
  • Molecular Biology

Background:

  • The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2) is a key regulator of cellular antioxidant responses.
  • NRF2 activation leads to increased glutathione and decreased reactive oxygen species (ROS).
  • Emerging evidence highlights NRF2's role in modulating metabolic processes crucial for cell proliferation and survival.

Purpose of the Study:

  • To review the intricate interplay between the NRF2/KEAP1 complex and cellular metabolism.
  • To discuss how metabolic pathway perturbations influence NRF2 stabilization.
  • To explore NRF2-mediated metabolic adaptations to cellular stress.

Main Methods:

  • Literature review focusing on NRF2, KEAP1, and metabolic pathways.
  • Analysis of NRF2's regulation of key metabolic pathways like the pentose phosphate pathway, glutaminolysis, and lipid metabolism.
  • Examination of NRF2-independent mechanisms of KEAP1 in metabolism.

Main Results:

  • NRF2 regulates metabolic pathways (pentose phosphate pathway, NADPH production, glutaminolysis, lipid/amino acid metabolism) often exploited by cancer cells.
  • Metabolic deregulation in normal and cancer physiology can stabilize NRF2.
  • Perturbations in TCA cycle, glycolysis, and autophagy can lead to NRF2 stabilization, which in turn helps cells manage metabolic stress.

Conclusions:

  • The NRF2/KEAP1 complex is deeply integrated with cellular metabolic processes.
  • Understanding this interplay is crucial for comprehending both normal physiology and cancer progression.
  • KEAP1 may exert metabolic influence beyond its canonical role in NRF2 regulation.
Keywords:
KEAP1NADPHNRF2amino acidscancer metabolismlipidsoxidative stress

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