Department of Pharmacology, School of Medicine, Daegu Catholic University, Daegu, 42472, Republic of Korea.
Department of Pharmacy, Graduate School of The Catholic University of Korea, Gyeonggi-do, 14662, Republic of Korea.
Arch Pharm Res. 2021 Mar;44(3):263-280. doi: 10.1007/s12272-021-01316-8. Epub 2021 Mar 22.
The transcription factor nuclear factor erythroid 2-like 2 (NEF2L2; NRF2) plays crucial roles in the defense system against electrophilic or oxidative stress by upregulating an array of genes encoding antioxidant proteins, electrophile/reactive oxygen species (ROS) detoxifying enzymes, and drug efflux transporters. In contrast to the protective roles in normal cells, the multifaceted role of NRF2 in tumor growth and progression, resistance to therapy and intratumoral stress, and metabolic adaptation is rapidly expanding, and the complex association of NRF2 with cancer signaling networks is being unveiled. In particular, the implication of NRF2 signaling in cancer stem cells (CSCs), a small population of tumor cells responsible for therapy resistance and tumor relapse, is emerging. Here, we described the dark side of NRF2 signaling in cancers discovered so far. A particular focus was put on the role of NRF2 in CSCs maintenance and therapy resistance, showing that low ROS levels and refractory drug response of CSCs are mediated by the activation of NRF2 signaling. A better understanding of the roles of the NRF2 pathway in CSCs will allow us to develop a novel therapeutic approach to control tumor relapse after therapy.
转录因子红系衍生 2 样 2（NEF2L2；NRF2）通过上调一系列编码抗氧化蛋白、亲电体/活性氧（ROS）解毒酶和药物外排转运体的基因，在抵御亲电性或氧化应激的防御系统中发挥着关键作用。与正常细胞中的保护作用相反，NRF2 在肿瘤生长和进展、对治疗的耐药性和肿瘤内应激以及代谢适应中的多方面作用正在迅速扩大，NRF2 与癌症信号网络的复杂关联也正在被揭示。特别是，NRF2 信号在癌症干细胞（CSC）中的作用正在显现，CSC 是一小部分负责治疗耐药性和肿瘤复发的肿瘤细胞。在这里，我们描述了迄今为止在癌症中发现的 NRF2 信号的阴暗面。特别关注的是 NRF2 在 CSCs 维持和治疗耐药性中的作用，表明 CSCs 中低 ROS 水平和耐药性药物反应是由 NRF2 信号的激活介导的。更好地理解 NRF2 通路在 CSCs 中的作用将使我们能够开发一种新的治疗方法来控制治疗后的肿瘤复发。
