Genetic, metabolic and immunological features of cancers with NRF2 addiction

Abstract

Nuclear factor erythroid‐derived 2‐like 2 (NRF2) is a master transcription factor that coordinately regulates the expression of many cytoprotective genes and plays a central role in defense mechanisms against oxidative and electrophilic insults. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental. Many human cancers exhibit persistent NRF2 activation and such cancer cells rely on NRF2 for most of their malignant characteristics, such as therapeutic resistance and aggressive tumourigenesis, and thus fall into NRF2 addiction. The persistent activation of NRF2 confers great advantages on cancer cells, whereas it is not tolerated by normal cells, suggesting that certain requirements are necessary for a cell to exploit NRF2 and evolve into malignant cancer cells. In this review, recent reports and data on the genetic, metabolic and immunological features of NRF2‐activated cancer cells are summarized, and prerequisites for NRF2 addiction in cancer cells and their therapeutic applications are discussed.

Immunoediting of KEAP1-NRF2 mutant tumours is required to circumvent NRF2-mediated immune surveillance

“…1 B and C). Consistent with this idea, a recent analysis by Kitamura et al revealed NRF2-activated LUSC tumours to be enriched in M2 macrophages, which are differentiated immune cells that are derived from monocytes [ 33 ]. These data from human tumours strongly suggest that NRF2-dependent recruitment of monocytes can play an important role during NRF2-dependent tumorigenesis.…”

Natural Compounds, Optimal Combination of Brusatol and Polydatin Promote Anti-Tumor Effect in Breast Cancer by Targeting Nrf2 Signaling Pathway

“…In addition, we now know that Nrf2 is widely recognized as an oxidative stress regulator, but numerous studies have shown that Nrf2 also has an essential role in cancer cell metabolism [55]. Activation of Nrf2 can participate in cancer cell metabolic processes and regulate multiple metabolism related key target genes, such as the production of NADPH, including the main enzymes catalyzing NADPH synthesis: G6PD, IDH1/IDH2, ME1, and PGD, as well as the regulation of the pentose phosphate pathway (PPP), and involved in the regulation of genes involved in glutathione metabolism and glutamine metabolism, among others [56,57]. According to Chio et al, combined targeting inhibition of Akt signaling and synthesis of glutathione could mimic Nrf2 ablation and effectively inhibit the survival of pancreatic ductal adenocarcinoma cells (PDACs) in vitro and in vivo [58].…”

The Role of Oxidative Stress in Tumorigenesis and Progression

“…Furthermore, sirtuin, including the SIRT1-SIRT3 axis, a kind of NAD + -consuming enzyme regarded as a stress responder, has been demonstrated to trigger metabolic reconstitution and affects the ROS level by deacetylating and activating metabolic enzymes and signaling molecules such as FOXO3a, PGC-1α, TFAM, Drp1, mTOR, and PINK1/Parkin [ 35 , 36 , 37 ]. In addition, ROS can activate NF-κB [ 38 ], NRF2 [ 38 , 39 ], and KHK-A [ 40 ] to reduce ROS production. Furthermore, ROS can directly regulate the function of metabolic enzymes through redox modification, which has been demonstrated in key redox-sensitive residues such as cysteine oxidation/S-sulfenylation/S-glutathionylation/S-nitrosylation and tyrosine nitration [ 4 ].…”