Nrf2 in Cancer, Detoxifying Enzymes and Cell Death Programs

Abstract

Reactive oxygen species (ROS) play an important role in cell proliferation and differentiation. They are also by-products of aerobic living conditions. Their inherent reactivity poses a threat for all cellular components. Cells have, therefore, evolved complex pathways to sense and maintain the redox balance. Among them, Nrf2 (Nuclear factor erythroid 2-related factor 2) plays a crucial role: it is activated under oxidative conditions and is responsible for the expression of the detoxification machinery and antiapoptotic factors. It is, however, a double edge sword: whilst it prevents tumorigenesis in healthy cells, its constitutive activation in cancer promotes tumour growth and metastasis. In addition, recent data have highlighted the importance of Nrf2 in evading programmed cell death. In this review, we will focus on the activation of the Nrf2 pathway in the cytoplasm, the molecular basis underlying Nrf2 binding to the DNA, and the dysregulation of this pathway in cancer, before discussing how Nrf2 contributes to the prevention of apoptosis and ferroptosis in cancer and how it is likely to be linked to detoxifying enzymes containing selenium.

Ferroptosis as a Novel Therapeutic Target for Diabetes and Its Complications

“…HSF1 negatively regulates PA-induced cell death, and HSF1 -/- mice treated with PA exhibited more serious ferroptosis by decreasing SLC40A1, FTH1, and Gpx4 expression and increasing TFRC expression in the heart ( 30 ). Nrf2, a transcription factor controlling the expression of many ferroptosis-related genes such as Gpx4, is generally considered to have an inhibitory effect on ferroptosis ( 99 ). An interesting study demonstrated that Nrf2 has detrimental effects on the heart by promoting ferroptosis during myocardial autophagy deficiency ( 100 ).…”

The molecular activity of cannabidiol in the regulation of Nrf2 system interacting with NF-κB pathway under oxidative stress

“…Nrf2 presents cytoprotective action resulting from a cellular response to stress conditions such as oxidative stress and inflammation caused by xenobiotics [ 44 ]. However, hyperactivity of Nrf2 has been found to be associated with cell differentiation and proliferation as well as malignant transformation and down-regulation of apoptosis [ 14 ]. Due to the Nrf2 activation causing ROS detoxification in cancer cells, which are characterized by a high level of ROS generation, as well as Nrf2-associated expression of anti-apoptotic factors such as anti-apoptotic protein Bcl-2 [ 45 ], Nrf2 has recently also been identified as an oncogene [ 14 ].…”

“…One of the key points to understanding the mechanism of action of cannabidiol under oxidative stress, which plays a key role in many diseases such as cardiovascular [ 9 ], metabolic [ 10 ], neurodegenerative [ 11 ] and cancerous [ 12 ], may be CBD-mediated regulation of nuclear factor-erythroid 2 factor 2 (Nrf2) pathway. The key role of the Nrf2 system is the modulation of antioxidant defense [ 13 ] and influences the regulation of molecular signaling involved in apoptosis, ferroptosis, tumor differentiation, and transformation [ 14 ]. These biological processes bring the link between the redox-modulating effect of CBD and Nrf2 pathway along.…”

Low-dose exposure to PBDE disrupts genomic integrity and innate immunity in mammary tissue

“…Also, innate immunity notwithstanding, the effects of PBDE on genomic disruption (i.e., more oxidative stress, less NHEJ DNA repair) are not ruled out as potential mediators in this latter experiment with C3(1)TAg mice. NFE2L2 (also known as NRF2) responds to oxidative stress to help prevent cancerous transformation of normal cells but is often up-regulated in established cancers and, thus, can be described as a double-edged sword (Jenkins and Gouge, 2021). As such, it is unclear whether PBDE may have caused NFE2L2 to up-regulate cytoprotective genes in fully transformed cells in C3(1)TAg mice.…”