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      The KEAP1-NRF2 pathway: Targets for therapy and role in cancer

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          Abstract

          The KEAP1-NRF2 pathway is the key regulator of cellular defense against both extrinsic and intrinsic oxidative and electrophilic stimuli. Since its discovery in the 1990s, its seminal role in various disease pathologies has become well appreciated, motivating research to elucidate the intricacies of NRF2 signaling and its downstream effects to identify novel targets for therapy. In this graphical review, we present an updated overview of the KEAP1-NRF2 signaling, focusing on the progress made within the past ten years. Specifically, we highlight the advances made in understanding the mechanism of activation of NRF2, resulting in novel discoveries in its therapeutic targeting. Furthermore, we will summarize new findings in the rapidly expanding field of NRF2 in cancer, with important implications for its diagnostics and treatment.

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          Oncogenic Signaling Pathways in The Cancer Genome Atlas

          Yuexin Liu, Ilya Shmulevich, Kalle Leinonen … (2018)
          Genetic alterations in signaling pathways that control cell cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in 10 canonical pathways: cell cycle, Hippo, Myc, Notch, NRF2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, P53 and β-catenin/WNT. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.
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            Oxidative Stress in Cancer

            John Hayes, Albena T. Dinkova-Kostova, Kenneth D. Tew (2020)
            Contingent upon concentration, reactive oxygen species (ROS) influence cancer evolution in apparently contradictory ways, either initiating/stimulating tumorigenesis and supporting transformation/proliferation of cancer cells or causing cell death. To accommodate high ROS levels, tumor cells modify sulfur-based metabolism, NADPH generation, and the activity of antioxidant transcription factors. During initiation, genetic changes enable cell survival under high ROS levels by activating antioxidant transcription factors or increasing NADPH via the pentose phosphate pathway (PPP). During progression and metastasis, tumor cells adapt to oxidative stress by increasing NADPH in various ways, including activation of AMPK, the PPP, and reductive glutamine and folate metabolism.
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              NRF2 and the Hallmarks of Cancer

              Donna Zhang, Montserrat Rojo de la Vega, Eli Chapman (2018)
              The transcription factor NRF2 is the master regulator of the cellular antioxidant response. Though recognized originally as a target of chemopreventive compounds that help prevent cancer and other maladies, accumulating evidence has established the NRF2 pathway as a driver of cancer progression, metastasis, and resistance to therapy. Recent studies have identified new functions for NRF2 in the regulation of metabolism and other essential cellular functions, establishing NRF2 as a truly pleiotropic transcription factor. In this review, we explore the roles of NRF2 in the hallmarks of cancer, indicating both tumor suppressive and tumor-promoting effects.
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                Author and article information

                Contributors
                Anna-Liisa Levonen
                Journal
                Journal ID (nlm-ta): Redox Biol
                Journal ID (iso-abbrev): Redox Biol
                Title: Redox Biology
                Publisher: Elsevier
                ISSN (Electronic): 2213-2317
                Publication date PMC-release: 29 April 2023
                Publication date Collection: July 2023
                Publication date (Electronic): 29 April 2023
                Volume: 63
                Electronic Location Identifier: 102726
                Affiliations
                [a ]A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70210, Kuopio, Finland
                [b ]Department of Pathology, Hospital Nova of Central Finland, Jyväskylä, 40620, Finland
                [c ]Science Service Center, Kuopio University Hospital, Kuopio, Finland
                Author notes
                [∗ ]Corresponding author. University of Eastern Finland, A.I.Virtanen Institute for Molecular Sciences, P.O.Box 1627, 70211 Kuopio, Finland. anna-liisa.levonen@ 123456uef.fi
                Article
                Publisher Item ID: S2213-2317(23)00127-1 Publisher ID: 102726
                DOI: 10.1016/j.redox.2023.102726
                PMC ID: 10189287
                PubMed ID: 37146513
                SO-VID: c2991eae-2dc6-4f4d-918f-787231d3b2f1
                Copyright © © 2023 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 30 March 2023
                Date revision received : 28 April 2023
                Date accepted : 28 April 2023
                Categories
                Subject: Review Article

                Keywords: nrf2,keap1,cancer,gene regulation
                Data availability:
                Keywords: nrf2, keap1, cancer, gene regulation

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