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.
Keywords: Cancer; Cancer stem cell; KEAP1; NRF2; Therapy resistance.