Modulation of NRF2 signaling pathway by nuclear receptors: Implications for cancer

Abstract

Nuclear factor-erythroid 2 p45-related factor 2 (NRF2, also known as Nfe2l2) plays a critical role in regulating cellular defense against electrophilic and oxidative stress by activating the expression of an array of antioxidant response element-dependent genes. On one hand, NRF2 activators have been used in clinical trials for cancer prevention and the treatment of diseases associated with oxidative stress; on the other hand, constitutive activation of NRF2 in many types of tumors contributes to the survival and growth of cancer cells, as well as resistance to anticancer therapy. In this review, we provide an overview of the NRF2 signaling pathway and discuss its role in carcinogenesis. We also introduce the inhibition of NRF2 by nuclear receptors. Further, we address the biological significance of regulation of the NRF2 signaling pathway by nuclear receptors in health and disease. Finally, we discuss the possible impact of NRF2 inhibition by nuclear receptors on cancer therapy.

Butylated hydroxyanisole induces distinct expression patterns of Nrf2 and detoxification enzymes in the liver and small intestine of C57BL/6 mice

“…It has been found recently that glycogen synthase kinase-3 (GSK-3) catalyzes phosphorylation of the Neh6 domain in Nrf2 leading to ubiquitylation of the CNCbZIP protein by βTrCP (Chowdhry et al, 2013). Nuclear receptors also modulate Nrf2 activity in the nucleus (Wang et al, 2007(Wang et al, , 2013Namani et al, 2014). The role of Nrf2 in up-regulating the expression of phase II enzymes and other cytoprotective proteins has been demonstrated in vivo using Nrf2 knock-out mice (Itoh et al, 1997;McMahon et al, 2001).…”

The Nuclear Factor (Erythroid-derived 2)-like 2 and Proteasome Maturation Protein Axis Mediate Bortezomib Resistance in Multiple Myeloma

“…Thus, our cell lines may serve to some extent as models of what is seen clinically, because retreatment with bortezomib, even in patients who had all previously responded well to this agent, produces response rates of only 50 -60% (54,55), indicating a rapid acquisition of resistance. Moreover, the involvement of POMP may provide some indication of why these patients have a poor overall prognosis, because both NRF2 (56) and POMP (30) have been linked to cellular defense mechanisms against electrophilic and oxidative stress. In that other drugs used against myeloma work in part by generating reactive oxygen species, including alkylating agents and anthracyclines, activation of the NRF2/POMP axis may reduce sensitivity to these other drug classes as well.…”

Applications of the Keap1–Nrf2 system for gene and cell therapy

“…In addition, inhibition of Nrf2 by various nuclear receptors has been suggested as a novel approach for cancer therapy [48] .…”