Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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The Multi-Faceted Consequences of NRF2 Activation throughout Carcinogenesis

  • Christopher J. Occhiuto (Department of Pharmacology and Toxicology, Michigan State University) ;
  • Jessica A. Moerland (Department of Pharmacology and Toxicology, Michigan State University) ;
  • Ana S. Leal (Department of Pharmacology and Toxicology, Michigan State University) ;
  • Kathleen A. Gallo (Department of Physiology, Michigan State University) ;
  • Karen T. Liby (Department of Pharmacology and Toxicology, Michigan State University)
  • Received : 2022.12.16
  • Accepted : 2023.02.22
  • Published : 2023.03.31
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Abstract

The oxidative balance of a cell is maintained by the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. This cytoprotective pathway detoxifies reactive oxygen species and xenobiotics. The role of the KEAP1/NRF2 pathway as pro-tumorigenic or anti-tumorigenic throughout stages of carcinogenesis (including initiation, promotion, progression, and metastasis) is complex. This mini review focuses on key studies describing how the KEAP1/NRF2 pathway affects cancer at different phases. The data compiled suggest that the roles of KEAP1/NRF2 in cancer are highly dependent on context; specifically, the model used (carcinogen-induced vs genetic), the tumor type, and the stage of cancer. Moreover, emerging data suggests that KEAP1/NRF2 is also important for regulating the tumor microenvironment and how its effects are amplified either by epigenetics or in response to co-occurring mutations. Further elucidation of the complexity of this pathway is needed in order to develop novel pharmacological tools and drugs to improve patient outcomes.

Keywords

Acknowledgement

This minireview is dedicated in memory of Michael B. Sporn, the "Father of Chemoprevention." The work was supported by NIH R01CA226690, MTRAC for Life Sciences Innovation Hub-Mi-Kickstart Award, the Breast Cancer Research Foundation, and the MSU Discretionary Funding Initiative (all to K.T.L.). Additional funding was provided by the Barnett Rosenberg Endowed Research Assistantship (J.A.M.), Aitch Foundation (J.A.M.), Integrative Pharmacological Sciences Training Program 5T32GM142521 (C.J.O.), and DOD Career Development Award LC210240 (A.S.L.).

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