Dissecting the Crosstalk between NRF2 Signaling and Metabolic Processes in Cancer

Abstract

The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes.

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

“…NADPH is an essential co-factor for both xenobiotic conjugation and antioxidant enzymes as well as a key element to switch cell metabolism toward the anabolic phase. Nrf2-regulated metabolic pathways indeed include the pentose phosphate pathway and stimulation of enzymes that cooperate with fatty acid biosynthesis [ 19 ]. The specific description of Nrf2 transcriptional targets is beyond the scope of this review but the papers by Liu et al and Ibrahim et al can provide more insights [ 20 , 21 ].…”

“…The pro-oncogenic function of Nrf2 signalling can be also due to its ability to modulate metabolic processes such as glucose metabolism, NADPH production, glutaminolysis, lipid and amino acid metabolism, which are somehow modified and utilized by cancer cells to guarantee proliferation and cell survival. A very nice and complete description in this regard has been provided by Lee [ 99 ] and De Blasi [ 19 ].…”

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

“…PI3K up-regulates NRF2 (nuclear factor erythroid 2) to support amino acid homeostasis through ATF4. It regulates the binding of ATF4 to the promoter of AsnS in the absence of its active inhibitor Keap1 [ 34 ]. NRF2 is generally a stress-responsive transcription factor that regulates a wide variety of genes involved in anabolic cancer metabolism, especially glucose and Gln metabolism.…”

The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers

“…While protecting normal cells, Nrf2 signaling also supports several transformed cells by enhancing the protection to cancer cells from oxidative damage, thereby facilitating their survival, migration, invasion, and progression to highly advanced stage tumors ( Figure 4 ). Nrf2 activation promotes the migration and invasion of cancer cells through the activation of transcription factor BTB and CNC homology 1 (BACH1), consequently promoting tumorigenesis [ 141 , 142 , 143 ].…”

“…While protecting normal cells, Nrf2 signaling also supports several transformed cells by enhancing the protection to cancer cells from oxidative damage, thereby facilitating their survival, migration, invasion, and progression to highly advanced stage tumors (Figure 4). Nrf2 activation promotes the migration and invasion of cancer cells through the activation of transcription factor BTB and CNC homology 1 (BACH1), consequently promoting tumorigenesis [141][142][143]. Nrf2 overexpression can induce the activation of glucose-6-phosphate dehydrogenase (G6PD)/HIF-1α signaling, consequently conferring the proliferation and metastasis of breast cancer cells via EMT signaling (epithelial-mesenchymal transition) due to Nrf2 overexpression can induce the activation of glucose-6-phosphate dehydrogenase (G6PD)/HIF-1α signaling, consequently conferring the proliferation and metastasis of breast cancer cells via EMT signaling (epithelial-mesenchymal transition) due to extensive NADPH levels [144].…”