The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives

Panieri, Emiliano; Telkoparan-Akillilar, Pelin; Süzen, Síbel; Saso, Luciano

doi:10.3390/biom10050791

Cited by 61 publications

(68 citation statements)

References 175 publications

(182 reference statements)

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“…Nrf2 is a key regulator of metabolism in cancer cells: Cancer cells acquire a resistance to oxidative, metabolic, and therapeutic insults through Nrf2/Keap1 signaling, which results in cytoprotective responses [ 124 ]. Metabolic reprogramming in cancer cells is typically correlated to the regulation of redox homeostasis, indicating that blocking the Nrf2 mediated metabolic network may be beneficial to impairing the growth of solid and hematological cancers [ 124 ]. For instance, metabolic reprogramming in cancer cells facilitated by mitochondria-mediated redox balance is linked to Nrf2 activity.…”

Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

“…For instance, Nrf2 could regulate the fatty acid oxidation and mitochondrial respiration in HEK-293T cells by controlling the expression levels of mitochondrial carnitine palmitoyltransferase isoforms (CPT1 and CPT2) and other gene expressions, viz., acyl-CoA oxidase 1 and 2 (ACOX1 and ACOX2) [ 128 , 129 ]. Nrf2 also confers changes in the mRNA expression levels of hepatic enzymes, viz., Elovl2,3,5,6 and Cyb5r3 and ATP-citrate lyase fatty acid synthases, but their effects are not validated yet in cancer cell models [ 124 ].…”

Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

“…Nrf2 activity is essential for the modulation of ATF4 pathways through the KRAS pathway by inducing nutrient deprivation via PI3K/Akt signaling in NSCLC cells [ 131 ]. Hence, the therapeutic modalities to inhibit KRAS-Nrf2-ATF4 signaling in these cancer cells may be a beneficial strategy to establish in clinical models [ 124 ]. Nrf2-addicted cancer cells could foster the cysteine uptake, i.e., coordinated with glutamate excretion and glutathione generation, which, consequently, limits the glutamate involved in anaplerosis of the Krebs cycle and reduces mitochondrial respiration.…”

Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

“…Finally, cancer cells rely upon the exogenous nonessential amino acids for their metabolism. These metabolic aspects provide significant clues to develop novel therapeutic modalities against Nrf2-addicted cancer cells [ 124 ].…”

Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

“…Nrf2 regulated redox homeostasis via the modulation of NADPH synthesis implicated in cancer cell antioxidant systems [ 124 ]. Mainly, Nrf2 activity directly or indirectly modulates the NADP+-dependent metabolic enzymes involved in the folate cycle or Krebs cycle or pentose phosphate pathway in Nrf2-addicted cancer cells.…”

Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

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

Beeraka

Bovilla

Doreswamy

et al. 2021

Cancers

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Glycated stress is mediated by the advanced glycation end products (AGE) and the binding of AGEs to the receptors for advanced glycation end products (RAGEs) in cancer cells. RAGEs are involved in mediating tumorigenesis of multiple cancers through the modulation of several downstream signaling cascades. Glycated stress modulates various signaling pathways that include p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa–B (NF-κB), tumor necrosis factor (TNF)-α, etc., which further foster the uncontrolled proliferation, growth, metastasis, angiogenesis, drug resistance, and evasion of apoptosis in several cancers. In this review, a balanced overview on the role of glycation and deglycation in modulating several signaling cascades that are involved in the progression of cancers was discussed. Further, we have highlighted the functional role of deglycating enzyme fructosamine-3-kinase (FN3K) on Nrf2-driven cancers. The activity of FN3K is attributed to its ability to deglycate Nrf2, a master regulator of oxidative stress in cells. FN3K is a unique protein that mediates deglycation by phosphorylating basic amino acids lysine and arginine in various proteins such as Nrf2. Deglycated Nrf2 is stable and binds to small musculoaponeurotic fibrosarcoma (sMAF) proteins, thereby activating cellular antioxidant mechanisms to protect cells from oxidative stress. This cellular protection offered by Nrf2 activation, in one way, prevents the transformation of a normal cell into a cancer cell; however, in the other way, it helps a cancer cell not only to survive under hypoxic conditions but also, to stay protected from various chemo- and radio-therapeutic treatments. Therefore, the activation of Nrf2 is similar to a double-edged sword and, if not controlled properly, can lead to the development of many solid tumors. Hence, there is a need to develop novel small molecule modulators/phytochemicals that can regulate FN3K activity, thereby maintaining Nrf2 in a controlled activation state.

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Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

Section: Nrf2 and Its Glycation And Deglycation Mechanisms In Regumentioning

confidence: 99%

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

Beeraka

Bovilla

Doreswamy

et al. 2021

Cancers

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Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas

et al. 2021

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Objectives To explore the clinical features, molecular characteristics, and immune landscape of lung adenocarcinoma patients with KEAP1/NFE2L2/CUL3 mutations. Methods The multi‐omics data from the GDC‐TCGA LUAD project of The Cancer Genome Atlas (TCGA) database were downloaded from the Xena browser. The estimate of the immune infiltration was implemented by using the GSVA analysis and CIBERSORT. The status of KEAP1/NFE2L2/CUL3 mutation in 50 LUAD samples of our department was detected by using Sanger sequencing, following the relative expression level of differentially expressed genes (DEGs), miRNAs (DEmiRNAs), and lncRNAs (DElncRNAs) was validated by IHC and real‐time quantitative polymerase chain reaction (RT‐qPCR). Results The Kaplan–Meier and multivariable Cox regression analyses demonstrated that KEAP1/NFE2L2/CUL3 mutations had independent prognostic value for OS and PFS in LUAD patients. The differential analysis detected 207 upregulated genes (like GSR/UGT1A6) and 447 downregulated genes (such as PIGR). GO, KEGG, and GSEA analyses demonstrated that DEGs were enriched in glutamate metabolism and the immune response. The constructed ceRNA network shows the linkage of differential lncRNAs and mRNAs. Three hundred and nine somatic mutations were detected, alterations in immune infiltration DNA methylations and stemness scores were also founded between the two groups. Eight mutated LUAD patients were detected by Sanger DNA sequencing in 50 surgical patients. GSR and UGT1A6 were validated to express higher in the Mut group, whereas the expression of PIGR was restrained. Furthermore, the IHC staining conducted on paraffin‐embedded tissue emphasizes the consistency of our result. Conclusion This research implemented the comprehensive analysis of KEAP1/NFE2L2/CUL3 somatic mutations in the LUAD patients. Compared with the wild type of LUAD patients, the Mut group shows a large difference in clinical features, RNA sequence, DNA methylation, and immune infiltrations, indicating complex mechanism oncogenesis and also reveals potential therapeutic targets.

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Neurological damages in COVID‐19 patients: Mechanisms and preventive interventions

Sarkar

Karmakar

Basu

et al. 2023

MedComm

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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a novel coronavirus, causes coronavirus disease 2019 (COVID‐19) which led to neurological damage and increased mortality worldwide in its second and third waves. It is associated with systemic inflammation, myocardial infarction, neurological illness including ischemic strokes (e.g., cardiac and cerebral ischemia), and even death through multi‐organ failure. At the early stage, the virus infects the lung epithelial cells and is slowly transmitted to the other organs including the gastrointestinal tract, blood vessels, kidneys, heart, and brain. The neurological effect of the virus is mainly due to hypoxia‐driven reactive oxygen species (ROS) and generated cytokine storm. Internalization of SARS‐CoV‐2 triggers ROS production and modulation of the immunological cascade which ultimately initiates the hypercoagulable state and vascular thrombosis. Suppression of immunological machinery and inhibition of ROS play an important role in neurological disturbances. So, COVID‐19 associated damage to the central nervous system, patients need special care to prevent multi‐organ failure at later stages of disease progression. Here in this review, we are selectively discussing these issues and possible antioxidant‐based prevention therapies for COVID‐19‐associated neurological damage that leads to multi‐organ failure.

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The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives

Cited by 61 publications

References 175 publications

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

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

Integrated analysis of patients with KEAP1/NFE2L2/CUL3 mutations in lung adenocarcinomas

Neurological damages in COVID‐19 patients: Mechanisms and preventive interventions

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