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The KEAP1–NRF2 System as a Molecular Target of Cancer Treatment

SIMPLE SUMMARY: Nuclear factor erythroid-derived 2-like 2 (encoded by the Nfe2l2 gene; NRF2) is a transcription factor that regulates a variety of cytoprotective genes, including antioxidant enzymes, detoxification enzymes, inflammation-related proteins, drug transporters and metabolic enzymes. NRF2...

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Detalles Bibliográficos
Autores principales: Taguchi, Keiko, Yamamoto, Masayuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795874/
https://www.ncbi.nlm.nih.gov/pubmed/33375248
http://dx.doi.org/10.3390/cancers13010046
Descripción
Sumario:SIMPLE SUMMARY: Nuclear factor erythroid-derived 2-like 2 (encoded by the Nfe2l2 gene; NRF2) is a transcription factor that regulates a variety of cytoprotective genes, including antioxidant enzymes, detoxification enzymes, inflammation-related proteins, drug transporters and metabolic enzymes. NRF2 is regulated by unique molecular mechanisms that stem from Kelch-like ECH-associated protein 1 (KEAP1) in response to oxidative and electrophilic stresses. It has been shown that disturbance or perturbation of the NRF2 activation causes and/or exacerbates many kinds of diseases. On the contrary, aberrant activations of NRF2 also provoke intriguing pathologic features, especially in cancers. Cancer cells with high NRF2 activity have been referred to as NRF2-addicted cancers, which are frequently found in lung cancers. In this review, we summarize the current accomplishments of the KEAP1–NRF2 pathway analyses in special reference to the therapeutic target of cancer therapy. The concept of synthetic lethality provides a new therapeutic approach for NRF2-addicted cancers. ABSTRACT: The Kelch-like ECH-associated protein 1 (KEAP1)—Nuclear factor erythroid-derived 2-like 2 (encoded by the Nfe2l2 gene; NRF2) system attracts extensive interest from scientists in basic and clinical cancer research fields, as NRF2 exhibits activity as both an oncogene and tumor suppressor, depending on the context. Especially unique and malignant, NRF2-addicted cancers exhibit high levels of NRF2 expression. Somatic mutations identified in the NRF2 or KEAP1 genes of NRF2-addicted cancers cause the stabilization and accumulation of NRF2. NRF2-addicted cancers hijack the intrinsic roles that NRF2 plays in cytoprotection, including antioxidative and anti-electrophilic responses, as well as metabolic reprogramming, and acquire a marked advantage to survive under severe and limited microenvironments. Therefore, NRF2 inhibitors are expected to have therapeutic effects in patients with NRF2-addicted cancers. In contrast, NRF2 activation in host immune cells exerts significant suppression of cancer cell growth, indicating that NRF2 inducers also have the potential to be therapeutics for cancers. Thus, the KEAP1–NRF2 system makes a broad range of contributions to both cancer development and suppression. These observations thus demonstrate that both NRF2 inhibitors and inducers are useful for the treatment of cancers with high NRF2 activity.