Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment

Abstract

The cap'n'collar (CNC) family serves as cellular sensors of oxidative and electrophilic stresses and shares structural similarities including basic leucine zipper (bZIP) and CNC domains. They form heterodimers with small MAF proteins to regulate antioxidant and phase II enzymes through antioxidant response element (ARE)-mediated transactivation. Among the CNC family members, NRF2 is required for systemic protection against redox-mediated injury and carcinogenesis. On the other hand, NRF2 is activated by oncogenic pathways, metabolism, and hypoxia. Constitutive NRF2 activation is observed in a variety of human cancers and it is highly correlated with tumor progression and aggressiveness. In this review, we will discuss how NRF2 plays dual roles in cancer prevention and progression depending on the cellular context and environment. Therefore, a better understanding of NRF2 will be necessary to exploit this complex network of balancing antioxidant pathways to inhibit tumor progression.

Keywords: ARE; Antioxidant response element; CNC family; Cancer; NRF2; Oxidative stress; Small MAF.

Figure 1. Structural domains of NRF2 and KEAP1

NRF2 includes the CNC-bZIP domain and functional Neh domains. The CNC-bZIP domain including Neh1 is required for DNA binding and interaction with ubiquitin conjugating enzymes. The TAD that consists of Neh5, Neh2 is involved n Keap1 binding [20]. KEAP1 contains the BTB domain for KEAP1 homodimerization and interaction with Cul3. Six kelch repeats in the Kelch/DGR domain interact with the Neh2 domain of NRF2 for binding. The IVR domain links the BTB and Kelch/DGR domains and has several critical cysteine residues for KEAP1 activation and NRF2 repression. Cysteine residues such as Cys151, Cys257, Cys273, Cys288, and Cys297 act as stress sensors to activate Keap1 and to repress NRF2 [25, 26]. Small MAF proteins utilize the highly conserved extended homology region (HER) for DNA binding [6]. The basic DNA binding domain and the leucine zipper dimerization domain are also required for their biological functions.

Figure 2. Oncogenic signaling pathways involved in NRF2 expression and activation

Oncogenic mutation of K-Ras, B-Raf, and Myc (K-Ras^G12D, B-Raf^V619E (corresponding to human B-Raf^V600E), and Myc^ERT2) increase Nfe2l2 transcription while reducing production of free radicals and DNA oxidation which results in enhanced cell proliferation and tumor burden [62]. Protein kinase C (PKC) and PKR-like ER kinase (PERK) also phosphorylate and activate NRF2 by inhibiting its binding to KEAP1 [65]. While inhibition of MAP kinases and PI3K reduce NRF2 nuclear translocation and ARE-dependent activation, a crosstalk between various signaling pathways may be involved in regulating NRF2 [–69].

Figure 3. Activation of NRF2 and HIF under various environmental stimuli

Hypoxia inhibits prolyl hydroxylation of HIFα, which leads to its stabilization and activation as a heterodimer transcription factor with HIFβ. Free radicals produced by oxidative stresses are also known to activate the HIF-pathway. NRF2, a main regulator of the antioxidative responses, has been recently recognized as a tumorigenic factor, which plays a role under hypoxia. In human colorectal cancer cells, when NRF2 is deficient, the HIF-VEGF pathway and tumor angiogenesis are inhibited, indicating that these two proteins may cooperate for tumor progression [105].