Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Abstract

Chemoresistance is a disturbing barrier in cancer therapy, which always results in limited therapeutic options and unfavorable prognosis. Nuclear factor E2-related factor 2 (NRF2) controls the expression of genes encoding cytoprotective enzymes and transporters that protect against oxidative stress and electrophilic injury to maintain intrinsic redox homeostasis. However, recent studies have demonstrated that aberrant activation of NRF2 due to genetic and/or epigenetic mutations in tumor contributes to the high expression of phase I and phase II drug-metabolizing enzymes, phase III transporters, and other cytoprotective proteins, which leads to the decreased therapeutic efficacy of anticancer drugs through biotransformation or extrusion during chemotherapy. Therefore, a better understanding of the role of NRF2 in regulation of these enzymes and transporters in tumors is necessary to find new strategies that improve chemotherapeutic efficacy. In this review, we summarized the recent findings about the chemoresistance-promoting role of NRF2, NRF2-regulated phase I and phase II drug-metabolizing enzymes, phase III drug efflux transporters, and other cytoprotective genes. Most importantly, the potential of NRF2 was proposed to counteract drug resistance in cancer treatment.

Keywords: KEAP1; NRF2 signaling pathway; cancer; chemotherapy; drug; inhibitors; mutations; strategy.