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.

Contributions of Nrf2 to Puerarin Prevention of Cardiac Hypertrophy and its Metabolic Enzymes Expression in Rats

“…Previous evidence suggests that Nrf2 may be a key transcription factor regulating the expression of genes for xenobiotic metabolism (Kensler et al, 2007). Nrf2 has been reported to upregulate the expression of UGT1A1 and UGT1A6 (Thimmulappa et al, 2002;Kundu et al, 2011;Bai et al, 2016). In our study, UGT1A1 and UGT1A9 mRNA and protein were detected in the livers and hearts of rats, as well as in NRCMs.…”

Emerging role of EPHX1 in chemoresistance of acute myeloid leukemia by regurlating drug‐metabolizing enzymes and apoptotic signaling

“…Nrf2 has been found to be an upstream signal of EPHX1 that drives EPHX1 transcription and regulates the resistance of cancer to chemotherapy . To examine whether Nrf2 expression is altered in response to ACM or MIT treatment, the expression of Nrf2 was measured by real‐time PCR and Western blot.…”

“…Nrf2 has been found to be an upstream signal of EPHX1 that drives EPHX1 transcription and regulates the resistance of cancer to chemotherapy. 21,22 In this study, we firstly analyzed the association of EPHX1 with clinicopathological parameters and prognosis, including cumulative incidence of relapse (CIR) and overall survival (OS) in AML patients, and examined the effect of EPHX1 on cell viability and apoptosis of AML in response to ACM and MIT. Besides, we preliminarily studied the relationship between EPHX1 and CYP1A1, GSTT1, GSTM1 in the metabolic pathway and the regulation of the upstream molecular Nrf2 in the signal pathway.…”

“…# P < 0.05, ## P < 0.01, ### P < 0.001 versus Vector + ACM or Vector + MIT. [Color figure can be viewed at wileyonlinelibrary.com] chemotherapy 21,22. To examine whether Nrf2 expression is altered in response to ACM or MIT treatment, the expression of Nrf2 was measured by real-time PCR and Western blot.…”

Keap1/Nrf2 impairing revised: are we missing the single nucleotide polymorphisms?

“…Genetic and epigenetic mechanisms of deregulation of the Keap1/ Nrf2 pathway have been described in solid tumors of different histogenesis, and have been evaluated in terms of their impact both on prognosis and response to chemoand radio-therapy (5,6). Somatic mutations of the KEAP1 and NFE2L2 genes and/or aberrant KEAP1 promoter hypermethylation were found to predominate in lung cancer, and, although less frequently, in head and neck cancer, biliary tracts cancer, gliomas and breast cancer (6)(7)(8)(9)(10)(11).…”