Shadows of NRF2 in cancer: Resistance to chemotherapy

• Published in: Current opinion in toxicology 2016-12, Vol.1, p.20-28
• Main Authors: Choi, Bo-hyun, Kwak, Mi-Kyoung
• Format: Article
• Language: English
• Subjects: Acquired resistance; Antioxidant proteins; Chemoresistance; Detoxifying enzymes; Drug efflux transporters; NRF2
• ISSN: 2468-2020; 2468-2020
• DOI: 10.1016/j.cotox.2016.08.003

Nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) plays a crucial role in the upregulation of a wide array of genes that are associated with the maintenance of intracellular redox homeostasis and xenobiotic detoxification. Although the beneficial effects of NRF2 activation have been demonstrated in various healthy cell systems, there is substantial evidence demonstrating the negative aspect of NRF2 in cancers. In this review, we discuss the evidence supporting that hyperactivation of NRF2 is associated with tumor resistance to a variety of anticancer drugs through detoxification of drug-induced reactive oxygen species and electrophiles, preventing cellular accumulation of drugs, and inhibiting drug-induced apoptotic responses. Intrinsic tumor resistance to chemotherapy could be brought about by the adaptive selection and amplification of tumor cells exhibiting high NRF2 expression under stress-rich microenvironment. More importantly, NRF2 can be upregulated by multiple anticancer drugs, suggesting a role of NRF2 in the immediate and reversible drug tolerant state and in the acquisition of permanent resistance. We also discuss the potential association of NRF2 overactivation with chemoresistance of tumor initiating cancer stem cells. Although NRF2 has been shown to play conflicting roles in healthy cells and cancer cells, the use of NRF2 as a predictive marker for chemosensitivity and the utility of NRF2 inhibitors as a cancer adjuvant therapy may facilitate improvements in tumor sensitivity to pharmacotherapy. •NRF2 is aberrantly activated in many types of cancers via multiple mechanisms.•NRF2 plays a critical role in chemoresistance of tumors by regulating multiple genes.•Anticancer efficacy of a wide range of chemotherapeutic drugs can be influenced by NRF2 activity.•NRF2 involves in the acquisition of drug-tolerance as well as permanent resistance to anticancer drugs.•NRF2 can be a promising target to predict tumor chemosensitivity and to overcome chemoresistance as an adjuvant therapy.