Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
College of Human Medicine, Michigan State University, East Lansing, MI 48824, USA.
Mol Cells. 2023 Mar 31;46(3):176-186. doi: 10.14348/molcells.2023.2191. Epub 2023 Mar 22.
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.
细胞的氧化平衡由 Kelch 样 ECH 相关蛋白 1（KEAP1）/核因子红细胞 2 相关因子 2（NRF2）途径维持。这种细胞保护途径可解毒活性氧和外源性化学物质。KEAP1/NRF2 途径在致癌作用的各个阶段（包括启动、促进、进展和转移）中的作用是复杂的，作为致癌或抑癌作用。本篇综述重点介绍了描述 KEAP1/NRF2 途径如何在不同阶段影响癌症的关键研究。编译的数据表明，KEAP1/NRF2 在癌症中的作用高度依赖于背景；具体而言，使用的模型（化学诱导与遗传）、肿瘤类型和癌症阶段。此外，新出现的数据表明，KEAP1/NRF2 对于调节肿瘤微环境也很重要，其作用通过表观遗传学或对共存突变的反应来放大。为了开发改善患者预后的新型药理学工具和药物，需要进一步阐明该途径的复杂性。
