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1.
Article in English | MEDLINE | ID: mdl-38772703

ABSTRACT

Redox reactions control fundamental biochemical processes, including energy production, metabolism, respiration, detoxification, and signal transduction. Cancer cells, due to their generally active metabolism for sustained proliferation, produce high levels of reactive oxygen species (ROS) compared to normal cells and are equipped with antioxidant defense systems to counteract the detrimental effects of ROS to maintain redox homeostasis. The KEAP1-NRF2 system plays a major role in sensing and regulating endogenous antioxidant defenses in both normal and cancer cells, creating a bivalent contribution of NRF2 to cancer prevention and therapy. Cancer cells hijack the NRF2-dependent antioxidant program and exploit a very unique metabolism as a trade-off for enhanced antioxidant capacity. This work provides an overview of redox metabolism in cancer cells, highlighting the role of the KEAP1-NRF2 system, selenoproteins, sulfur metabolism, heme/iron metabolism, and antioxidants. Finally, we describe therapeutic approaches that can be leveraged to target redox metabolism in cancer.

2.
Am J Transplant ; 24(2): 293-303, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37734444

ABSTRACT

Donor shortage is a major problem in lung transplantation (LTx), and the use of lungs from elderly donors is one of the possible solutions in a rapidly aging population. However, the utilization of organs from donors aged >65 years has remained infrequent and may be related to a poor outcome. To investigate the molecular events in grafts from elderly donors early after LTx, the left lungs of young and old mice were subjected to 1 hour of ischemia and subsequent reperfusion. The left lungs were collected at 1 hour, 1 day, and 3 days after reperfusion and subjected to wet-to-dry weight ratio measurement, histological analysis, and molecular biological analysis, including RNA sequencing. The lungs in old mice exhibited more severe and prolonged pulmonary edema than those in young mice after ischemia reperfusion, which was accompanied by upregulation of the genes associated with inflammation and impaired expression of cell cycle-related genes. Apoptotic cells increased and proliferating type 2 alveolar epithelial cells decreased in the lungs of old mice compared with young mice. These factors could become conceptual targets for developing interventions to ameliorate lung ischemia-reperfusion injury after LTx from elderly donors, which may serve to expand the old donor pool.


Subject(s)
Lung Injury , Lung Transplantation , Reperfusion Injury , Animals , Mice , Aging , Inflammation/pathology , Ischemia/pathology , Lung Injury/pathology , Lung Transplantation/methods , Reperfusion Injury/pathology
3.
Br J Pharmacol ; 2023 Sep 15.
Article in English | MEDLINE | ID: mdl-37715470

ABSTRACT

The KEAP1-NRF2 system plays a central role in cytoprotection in defence mechanisms against oxidative stress. The KEAP1-NRF2 system has been regarded as a sulfur-utilizing cytoprotective mechanism, because KEAP1 serves as a biosensor for electrophiles by using its reactive thiols and NRF2 is a transcriptional factor regulating genes involved in sulfur-mediated redox reactions. NRF2 is a key regulator of cytoprotective genes, such as antioxidant and detoxification genes, and also possesses potent anti-inflammatory activity. Recently NRF2 has been the focus of attention as a regulator of cellular metabolism and mitochondrial function. The NRF2-mediated regulatory mechanisms of metabolites and mitochondria have been considered diverse, but have not yet been fully clarified. This review article provides an overview of molecular mechanisms that regulate NRF2 signalling and its cytoprotective roles, and highlights NRF2 contribution to cellular metabolism, particularly in the context of mitochondrial function and newly-found sulfur metabolism.

4.
J Biochem ; 171(5): 567-578, 2022 May 11.
Article in English | MEDLINE | ID: mdl-35137113

ABSTRACT

NRF2 is a transcription activator that plays a key role in cytoprotection against oxidative stress. Although increased NRF2 activity is principally beneficial for our health, NRF2 activation in cancer cells is detrimental, as it drives their malignant progression. We previously found that CCAAT/enhancer-binding protein B (CEBPB) cooperates with NRF2 in NRF2-activated lung cancer and enhances tumour-initiating activity by promoting NOTCH3 expression. However, the general contribution of CEBPB in lung cancer is rather controversial, probably because the role of CEBPB depends on cooperating transcription factors in each cellular context. To understand how NRF2 shapes the function of CEBPB in NRF2-activated lung cancers and its biological consequence, we comprehensively explored NRF2-CEBPB-coregulated genes and found that genes involved in drug metabolism and detoxification were characteristically enriched. Indeed, CEBPB and NRF2 cooperatively contribute to the drug resistance. We also found that CEBPB is directly regulated by NRF2, which is likely to be advantageous for the coexpression and cooperative function of NRF2 and CEBPB. These results suggest that drug resistance of NRF2-activated lung cancers is achieved by the cooperative function of NRF2 and CEBPB.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , CCAAT-Enhancer-Binding Protein-beta/genetics , CCAAT-Enhancer-Binding Protein-beta/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Drug Resistance , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Receptors, Fc , Signal Transduction
6.
Nat Commun ; 11(1): 5911, 2020 11 20.
Article in English | MEDLINE | ID: mdl-33219226

ABSTRACT

Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.


Subject(s)
CCAAT-Enhancer-Binding Protein-beta/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , NF-E2-Related Factor 2/metabolism , Carcinogenesis/genetics , Carcinogens , Cell Line, Tumor , Enhancer Elements, Genetic , Epigenomics , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/genetics , Signal Transduction
7.
Biophys Rev ; 12(2): 435-441, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32112372

ABSTRACT

The KEAP1-NRF2 system is a sulfur-employing defense mechanism against oxidative and electrophilic stress. NRF2 is a potent transcription activator for genes mediating sulfur-involving redox reactions, and KEAP1 controls the NRF2 activity in response to the stimuli by utilizing reactivity of sulfur atoms. In many human cancer cells, the KEAP1-mediated regulation of NRF2 activity is abrogated, resulting in the persistent activation of NRF2. Persistently activated NRF2 drives malignant progression of cancers by increasing therapeutic resistance and promoting aggressive tumorigenesis, a state termed as NRF2 addiction. In NRF2-addicted cancer cell, NRF2 contributes to metabolic reprogramming in cooperation with other oncogenic pathways. In particular, NRF2 strongly activates cystine uptake coupled with glutamate excretion and glutathione synthesis, which increases consumption of intracellular glutamate. Decreased availability of glutamate limits anaplerosis of the TCA cycle, resulting in low mitochondrial respiration, and nitrogen source, resulting in the high dependency on exogenous non-essential amino acids. The highly enhanced glutathione synthesis is also likely to alter sulfur metabolism, which can contribute to the maintenance of the mitochondrial membrane potential in normal cells. The potent antioxidant and detoxification capacity supported by abundant production of glutathione is achieved at the expense of central carbon metabolism and requires skewed metabolic flow of sulfur. These metabolic features of NRF2 addiction status provide clues for novel therapeutic strategies to target NRF2-addicted cancer cells.

8.
Mol Cell Biol ; 38(17)2018 09 01.
Article in English | MEDLINE | ID: mdl-29941490

ABSTRACT

Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors. A major cause of this resistance is the proteasome bounce-back response mediated by NRF1, a transcription factor that coordinately activates proteasome subunit genes. To identify new targets for efficient suppression of UPS, we explored, using immunoprecipitation and mass spectrometry, the possible existence of nuclear proteins that cooperate with NRF1 and identified O-linked N-acetylglucosamine transferase (OGT) and host cell factor C1 (HCF-1) as two proteins capable of forming a complex with NRF1. O-GlcNAcylation catalyzed by OGT was essential for NRF1 stabilization and consequent upregulation of proteasome subunit genes. Meta-analysis of breast and colorectal cancers revealed positive correlations in the relative protein abundance of OGT and proteasome subunits. OGT inhibition was effective at sensitizing cancer cells to a proteasome inhibitor both in culture cells and a xenograft mouse model. Since active O-GlcNAcylation is a feature of cancer metabolism, our study has clarified a novel linkage between cancer metabolism and UPS function and added a new regulatory axis to the regulation of the proteasome activity.


Subject(s)
NF-E2-Related Factor 1/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Proteasome Inhibitors/pharmacology , Acetylglucosamine/metabolism , Animals , Cell Line, Tumor , Drug Resistance, Neoplasm/physiology , Female , Glycosylation , HEK293 Cells , HeLa Cells , Host Cell Factor C1/chemistry , Host Cell Factor C1/genetics , Host Cell Factor C1/metabolism , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Nude , N-Acetylglucosaminyltransferases/antagonists & inhibitors , N-Acetylglucosaminyltransferases/genetics , N-Acetylglucosaminyltransferases/metabolism , NF-E2-Related Factor 1/chemistry , NF-E2-Related Factor 1/genetics , Neoplasms/genetics , Nuclear Respiratory Factor 1 , Promoter Regions, Genetic , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism , Protein Interaction Domains and Motifs , Protein Stability , Ubiquitin/metabolism , Xenograft Model Antitumor Assays , beta-Transducin Repeat-Containing Proteins/chemistry , beta-Transducin Repeat-Containing Proteins/metabolism
9.
J Biol Chem ; 292(18): 7519-7530, 2017 05 05.
Article in English | MEDLINE | ID: mdl-28314773

ABSTRACT

NRF2 (nuclear factor erythroid 2-related factor 2) is a key transcriptional activator that mediates the inducible expression of antioxidant genes. NRF2 is normally ubiquitinated by KEAP1 (Kelch-like ECH-associated protein 1) and subsequently degraded by proteasomes. Inactivation of KEAP1 by oxidative stress or electrophilic chemicals allows NRF2 to activate transcription through binding to antioxidant response elements (AREs) and recruiting histone acetyltransferase CBP (CREB-binding protein). Whereas KEAP1-dependent regulation is a major determinant of NRF2 activity, NRF2-mediated transcriptional activation varies from context to context, suggesting that other intracellular signaling cascades may impact NRF2 function. To identify a signaling pathway that modifies NRF2 activity, we immunoprecipitated endogenous NRF2 and its interacting proteins from mouse liver and identified glucocorticoid receptor (GR) as a novel NRF2-binding partner. We found that glucocorticoids, dexamethasone and betamethasone, antagonize diethyl maleate-induced activation of NRF2 target genes in a GR-dependent manner. Dexamethasone treatment enhanced GR recruitment to AREs without affecting chromatin binding of NRF2, resulting in the inhibition of CBP recruitment and histone acetylation at AREs. This repressive effect was canceled by the addition of histone deacetylase inhibitors. Thus, GR signaling decreases NRF2 transcriptional activation through reducing the NRF2-dependent histone acetylation. Consistent with these observations, GR signaling blocked NRF2-mediated cytoprotection from oxidative stress. This study suggests that an impaired antioxidant response by NRF2 and a resulting decrease in cellular antioxidant capacity account for the side effects of glucocorticoids, providing a novel viewpoint for the pathogenesis of hypercorticosteroidism.


Subject(s)
Dexamethasone/pharmacology , Histones/metabolism , NF-E2-Related Factor 2/metabolism , Receptors, Glucocorticoid/metabolism , Signal Transduction/drug effects , Acetylation/drug effects , Animals , Histones/genetics , Kelch-Like ECH-Associated Protein 1/genetics , Kelch-Like ECH-Associated Protein 1/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Knockout , NF-E2-Related Factor 2/genetics , Oxidative Stress/drug effects , Phosphoproteins/genetics , Phosphoproteins/metabolism , Receptors, Glucocorticoid/genetics
10.
Mol Cell Biol ; 36(3): 407-20, 2016 02 01.
Article in English | MEDLINE | ID: mdl-26572828

ABSTRACT

The KEAP1-NRF2 system plays a central role in cytoprotection. NRF2 is stabilized in response to electrophiles and activates transcription of antioxidant genes. Although robust induction of NRF2 target genes confers resistance to oxidative insults, how NRF2 triggers transcriptional activation after binding to DNA has not been elucidated. To decipher the molecular mechanisms underlying NRF2-dependent transcriptional activation, we purified the NRF2 nuclear protein complex and identified the Mediator subunits as NRF2 cofactors. Among them, MED16 directly associated with NRF2. Disruption of Med16 significantly attenuated the electrophile-induced expression of NRF2 target genes but did not affect hypoxia-induced gene expression, suggesting a specific requirement for MED16 in NRF2-dependent transcription. Importantly, we found that 75% of NRF2-activated genes exhibited blunted inductions by electrophiles in Med16-deficient cells compared to wild-type cells, which strongly argues that MED16 is a major contributor supporting NRF2-dependent transcriptional activation. NRF2-dependent phosphorylation of the RNA polymerase II C-terminal domain was absent in Med16-deficient cells, suggesting that MED16 serves as a conduit to transmit NRF2-activating signals to RNA polymerase II. MED16 indeed turned out to be essential for cytoprotection against oxidative insults. Thus, the KEAP1-NRF2-MED16 axis has emerged as a new regulatory pathway mediating the antioxidant response through the robust activation of NRF2 target genes.


Subject(s)
Gene Expression Regulation , Mediator Complex/metabolism , NF-E2-Related Factor 2/metabolism , Protein Interaction Maps , Animals , Cell Line , Cell Proliferation , Gene Knockout Techniques , Humans , Liver/metabolism , Mediator Complex/chemistry , Mediator Complex/genetics , Mice , NF-E2-Related Factor 2/genetics , Oxidative Stress , Phosphorylation , Protein Interaction Domains and Motifs , RNA Polymerase II/metabolism , Signal Transduction
11.
Nihon Kokyuki Gakkai Zasshi ; 49(10): 760-4, 2011 Oct.
Article in Japanese | MEDLINE | ID: mdl-22117314

ABSTRACT

A 78-year-old man with COPD was admitted in August 2010 complaining of productive cough and fever of 38 degrees C for 2 days. He was admitted with septic shock and pneumonia of the right upper lobe. Despite antibiotic administration, infiltration progressed to the right lung and lower left lung after 24 hours, and he developed acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation. All cultures from both sputum and blood grew Acinetobacter baumannii. He recovered following intensive care. Although some community-acquired pneumonias by A. baumannii are reported in Japan, this is the first report concerning a successfully treated patient.


Subject(s)
Acinetobacter Infections/microbiology , Acinetobacter baumannii/isolation & purification , Community-Acquired Infections/microbiology , Pneumonia, Bacterial/microbiology , Aged , Disseminated Intravascular Coagulation/microbiology , Humans , Shock, Septic/microbiology
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