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1
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Zhang DD. Thirty years of NRF2: advances and therapeutic challenges. Nat Rev Drug Discov 2025:10.1038/s41573-025-01145-0. [PMID: 40038406 DOI: 10.1038/s41573-025-01145-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/23/2025] [Indexed: 03/06/2025]
Abstract
Over the last 30 years, NRF2 has evolved from being recognized as a transcription factor primarily involved in redox balance and detoxification to a well-appreciated master regulator of cellular proteostasis, metabolism and iron homeostasis. NRF2 plays a pivotal role in diverse pathologies, including cancer, and metabolic, inflammatory and neurodegenerative disorders. It exhibits a Janus-faced duality, safeguarding cellular integrity in normal cells against environmental insults to prevent disease onset, whereas in certain cancers, constitutively elevated NRF2 levels provide a tumour survival advantage, promoting progression, therapy resistance and metastasis. Advances in understanding the mechanistic regulation of NRF2 and its roles in human pathology have propelled the investigation of NRF2-targeted therapeutic strategies. This Review dissects the mechanistic intricacies of NRF2 signalling, its cross-talk with biological processes and its far-reaching implications for health and disease, highlighting key discoveries that have shaped innovative therapeutic approaches targeting NRF2.
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Affiliation(s)
- Donna D Zhang
- Department of Molecular Medicine, Center for Inflammation Science and Systems Medicine, UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL, USA.
- University of Florida Health Cancer Center, University of Florida, Gainesville, FL, USA.
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2
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Dong XM, Chen L, Xu YX, Wu P, Xie T, Liu ZQ. Exploring metabolic reprogramming in esophageal cancer: the role of key enzymes in glucose, amino acid, and nucleotide pathways and targeted therapies. Cancer Gene Ther 2025; 32:165-183. [PMID: 39794467 DOI: 10.1038/s41417-024-00858-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 01/13/2025]
Abstract
Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.
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Affiliation(s)
- Xue-Man Dong
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
| | - Lin Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
| | - Yu-Xin Xu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
| | - Pu Wu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.
| | - Zhao-Qian Liu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
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3
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Oshikiri H, Taguchi K, Hirose W, Taniyama Y, Kamei T, Siegel D, Ross D, Kitson RRA, Baird L, Yamamoto M. Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal Squamous Cell Carcinoma. Mol Cell Biol 2024; 45:79-97. [PMID: 39717011 DOI: 10.1080/10985549.2024.2438817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/27/2024] [Accepted: 12/02/2024] [Indexed: 12/25/2024] Open
Abstract
In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity. As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione conjugation-mediated hepatotoxicity. In this study, using a variety of in vitro and in vivo cancer models, we found that C19-substituted 17DMAG compounds maintain their enhanced toxicity profile and synthetic lethal interaction with NRF2-NQO1-activated cancer cells. Importantly, using a xenograft mouse tumor model, we found that C19-substituted 17DMAG displayed significant anticancer efficacy against NRF2-NQO1-activated cancer cells without causing hepatotoxicity. These results clearly demonstrate the improved clinical potential for this new class of HSP90 inhibitor anticancer drugs, and suggest that patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.
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Affiliation(s)
- Hiroyuki Oshikiri
- Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keiko Taguchi
- Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Wataru Hirose
- Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yusuke Taniyama
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - David Siegel
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - David Ross
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Russell R A Kitson
- Department of Organic and Bioorganic Chemistry, Charles University, Hradec Králové, Czech Republic
| | - Liam Baird
- Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
| | - Masayuki Yamamoto
- Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
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4
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Zoccarato A, Smyrnias I, Reumiller CM, Hafstad AD, Chong M, Richards DA, Santos CXC, Visnagri A, Verma S, Bromage DI, Zhang M, Zhang X, Sawyer G, Thompson R, Shah AM. NRF2 activation in the heart induces glucose metabolic reprogramming and reduces cardiac dysfunction via upregulation of the pentose phosphate pathway. Cardiovasc Res 2024:cvae250. [PMID: 39657243 DOI: 10.1093/cvr/cvae250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 08/02/2024] [Accepted: 12/05/2024] [Indexed: 12/17/2024] Open
Abstract
AIMS The transcription factor NRF2 is well recognized as a master regulator of antioxidant responses and cytoprotective genes. Previous studies showed that NRF2 enhances resistance of mouse hearts to chronic hemodynamic overload at least in part by reducing oxidative stress. Evidence from other tissues suggests that NRF2 may modulate glucose intermediary metabolism but whether NRF2 has such effects in the heart is unclear. Here, we investigate the role of NRF2 in regulating glucose intermediary metabolism and cardiac function during disease stress. METHODS AND RESULTS Cardiomyocyte-specific Keap1 knockout (csKeap1KO) mice, deficient in the endogenous inhibitor of NRF2, were used as a novel model of constitutively active NRF2 signaling. Targeted metabolomics and isotopomer analysis were employed in studies with 13C6-glucose in csKeap1KO and wild-type (WT) mice. Pharmacological and genetic approaches were utilized in neonatal rat ventricular cardiomyocytes (NRVM) to explore molecular mechanisms. We found that cardiac-specific activation of NRF2 redirected glucose metabolism towards the pentose phosphate pathway (PPP), a branch pathway of glycolysis, and mitigated pressure overload-induced cardiomyocyte death and cardiac dysfunction. Activation of NRF2 also protected against myocardial infarction-induced DNA damage in remote myocardium and cardiac dysfunction. In vitro, knockdown of Keap1 upregulated PPP enzymes and reduced cell death in NRVM subjected to chronic neurohumoral stimulation. These pro-survival effects were abolished by pharmacological inhibition of the PPP or silencing of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of NRF2 in NRVM increased stress-induced DNA damage which was rescued by supplementing the cells with either NADPH or nucleosides, the two main products of the PPP. CONCLUSIONS These results indicate that NRF2 regulates cardiac metabolic reprogramming by stimulating the diversion of glucose into the PPP, thereby generating NADPH and providing nucleotides to prevent stress-induced DNA damage and cardiac dysfunction.
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Affiliation(s)
- Anna Zoccarato
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Ioannis Smyrnias
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
- Comparative Biomedical Sciences, University of Surrey, Guildford, UK
| | - Christina M Reumiller
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Anne D Hafstad
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
- Cardiovascular Research Group, Department of Medical Biology, UiT, The Arctic University of Norway, Tromsø, Norway
| | - Mei Chong
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Daniel A Richards
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Celio X C Santos
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Asjad Visnagri
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Sharwari Verma
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Daniel I Bromage
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Min Zhang
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Xiaohong Zhang
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Greta Sawyer
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Richard Thompson
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
| | - Ajay M Shah
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre of Excellence, London, UK
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5
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Ham S, Choi BH, Kwak MK. NRF2 signaling and amino acid metabolism in cancer. Free Radic Res 2024; 58:648-661. [PMID: 39540796 DOI: 10.1080/10715762.2024.2423690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 10/02/2024] [Accepted: 10/19/2024] [Indexed: 11/16/2024]
Abstract
Alterations in amino acid metabolism have emerged as a critical component in cancer biology, influencing various aspects of tumor initiation, progression, and metastasis. This review explores how amino acids, beyond their role as protein building blocks, are essential for redox balance, cell proliferation, metastasis, signaling/epigenetic regulation, and tumor microenvironment modulation in cancer. We particularly focus on the intricate relationship between amino acid metabolism and nuclear factor erythroid 2-related factor 2 (NRF2) signaling, a master regulator of oxidative stress response that frequently hyperactivated in cancer. Increasing evidence indicates that NRF2 is a key player in amino acid metabolism, orchestrating metabolism of cysteine, glutamine, and serine/glycine to promote cancer cell survival and growth. This comprehensive analysis provides insights into potential therapeutic strategies targeting the NRF2-amino acid metabolism axis, offering new avenues for cancer treatment that address multiple aspects of tumor biology.
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Affiliation(s)
- Suji Ham
- Department of Pharmacology, School of Medicine, Daegu Catholic University, Daegu, Republic of Korea
| | - Bo-Hyun Choi
- Department of Pharmacology, School of Medicine, Daegu Catholic University, Daegu, Republic of Korea
| | - Mi-Kyoung Kwak
- College of Pharmacy, The Catholic University of Korea, Bucheon, Republic of Korea
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6
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Luchkova A, Mata A, Cadenas S. Nrf2 as a regulator of energy metabolism and mitochondrial function. FEBS Lett 2024; 598:2092-2105. [PMID: 39118293 DOI: 10.1002/1873-3468.14993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 06/13/2024] [Accepted: 06/27/2024] [Indexed: 08/10/2024]
Abstract
Nuclear factor erythroid-2-related factor 2 (Nrf2) is essential for the control of cellular redox homeostasis. When activated, Nrf2 elicits cytoprotective effects through the expression of several genes encoding antioxidant and detoxifying enzymes. Nrf2 can also improve antioxidant defense via the pentose phosphate pathway by increasing NADPH availability to regenerate glutathione. Microarray and genome-wide localization analyses have identified many Nrf2 target genes beyond those linked to its redox-regulatory capacity. Nrf2 regulates several intermediary metabolic pathways and is involved in cancer cell metabolic reprogramming, contributing to malignant phenotypes. Nrf2 also modulates substrate utilization for mitochondrial respiration. Here we review the experimental evidence supporting the essential role of Nrf2 in the regulation of energy metabolism and mitochondrial function.
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Affiliation(s)
- Alina Luchkova
- Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Cantoblanco, Madrid, Spain
| | - Ana Mata
- Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Cantoblanco, Madrid, Spain
| | - Susana Cadenas
- Centro de Biología Molecular Severo Ochoa (CSIC/UAM), Cantoblanco, Madrid, Spain
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7
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Karunatilleke NC, Brickenden A, Choy WY. Molecular basis of the interactions between the disordered Neh4 and Neh5 domains of Nrf2 and CBP/p300 in oxidative stress response. Protein Sci 2024; 33:e5137. [PMID: 39150085 PMCID: PMC11328122 DOI: 10.1002/pro.5137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 06/21/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor that functions in maintaining redox homeostasis in cells. It mediates the transcription of cytoprotective genes in response to environmental and endogenous stresses to prevent oxidative damage. Thus, Nrf2 plays a significant role in chemoprevention. However, aberrant activation of Nrf2 has been shown to protect cancer cells from apoptosis and contribute to their chemoresistance. The interaction between Nrf2 and CBP is critical for the gene transcription activation. CBP and its homologue p300 interact with two transactivation domains in Nrf2, Neh4, and Neh5 domains through their TAZ1 and TAZ2 domains. To date, the molecular basis of this crucial interaction is not known, hindering a more detailed understanding of the regulation of Nrf2. To close this knowledge gap, we have used a set of biophysical experiments to dissect the Nrf2-CBP/p300 interactions. Structural properties of Neh4 and Neh5 and their binding with the TAZ1 and TAZ2 domains of CBP/p300 were characterized. Our results show that the Neh4 and Neh5 domains of Nrf2 are intrinsically disordered, and they both can bind the TAZ1 and TAZ2 domains of CBP/p300 with micromolar affinities. The findings provide molecular insight into the regulation of Nrf2 by CBP/p300 through multi-domain interactions.
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Affiliation(s)
- Nadun C Karunatilleke
- Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada
| | - Anne Brickenden
- Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada
| | - Wing-Yiu Choy
- Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada
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8
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Neagu M, Constantin C, Surcel M, Munteanu A, Scheau C, Savulescu‐Fiedler I, Caruntu C. Diabetic neuropathy: A NRF2 disease? J Diabetes 2024; 16:e13524. [PMID: 38158644 PMCID: PMC11418408 DOI: 10.1111/1753-0407.13524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 11/10/2023] [Accepted: 12/06/2023] [Indexed: 01/03/2024] Open
Abstract
The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) has multifarious action with its target genes having redox-regulating functions and being involved in inflammation control, proteostasis, autophagy, and metabolic pathways. Therefore, the genes controlled by NRF2 are involved in the pathogenesis of myriad diseases, such as cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, autoimmune disorders, and cancer. Amidst this large array of diseases, diabetic neuropathy (DN) occurs in half of patients diagnosed with diabetes and appears as an injury inflicted upon peripheral and autonomic nervous systems. As a complex effector factor, NRF2 has entered the spotlight during the search of new biomarkers and/or new therapy targets in DN. Due to the growing attention for NRF2 as a modulating factor in several diseases, including DN, this paper aims to update the recently discovered regulatory pathways of NRF2 in oxidative stress, inflammation and immunity. It presents the animal models that further facilitated the human studies in regard to NRF2 modulation and the possibilities of using NRF2 as DN biomarker and/or as target therapy.
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Affiliation(s)
- Monica Neagu
- Immunology DepartmentVictor Babes National Institute of PathologyBucharestRomania
- Pathology DepartmentColentina Clinical HospitalBucharestRomania
- Doctoral School, Faculty of BiologyUniversity of BucharestBucharestRomania
| | - Carolina Constantin
- Immunology DepartmentVictor Babes National Institute of PathologyBucharestRomania
- Pathology DepartmentColentina Clinical HospitalBucharestRomania
| | - Mihaela Surcel
- Immunology DepartmentVictor Babes National Institute of PathologyBucharestRomania
| | - Adriana Munteanu
- Immunology DepartmentVictor Babes National Institute of PathologyBucharestRomania
| | - Cristian Scheau
- Department of Physiology“Carol Davila” University of Medicine and PharmacyBucharestRomania
| | - Ilinca Savulescu‐Fiedler
- Department of Internal Medicine – Coltea Clinical Hospital, ”Carol Davila” University of Medicine and PharmacyBucharestRomania
| | - Constantin Caruntu
- Department of Physiology“Carol Davila” University of Medicine and PharmacyBucharestRomania
- Department of Dermatology“Prof. N.C. Paulescu” National Institute of Diabetes, Nutrition and Metabolic DiseasesBucharestRomania
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9
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Borović Šunjić S, Jaganjac M, Vlainić J, Halasz M, Žarković N. Lipid Peroxidation-Related Redox Signaling in Osteosarcoma. Int J Mol Sci 2024; 25:4559. [PMID: 38674143 PMCID: PMC11050283 DOI: 10.3390/ijms25084559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including osteosarcoma, express altered redox signaling pathways. Such redox signaling pathways protect cancer cells from the cytotoxic effects of oxidative stress, thus supporting malignant transformation, and eventually from cytotoxic anticancer therapies associated with oxidative stress. In this review, we aim to explore the status of lipid peroxidation in osteosarcoma and highlight the involvement of lipid peroxidation products in redox signaling pathways, including the involvement of lipid peroxidation in osteosarcoma therapies.
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Affiliation(s)
- Suzana Borović Šunjić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruder Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia; (M.J.); (J.V.); (M.H.)
| | | | | | | | - Neven Žarković
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruder Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia; (M.J.); (J.V.); (M.H.)
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10
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Wu D, Zhang K, Khan FA, Pandupuspitasari NS, Guan K, Sun F, Huang C. A comprehensive review on signaling attributes of serine and serine metabolism in health and disease. Int J Biol Macromol 2024; 260:129607. [PMID: 38253153 DOI: 10.1016/j.ijbiomac.2024.129607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 01/17/2024] [Accepted: 01/17/2024] [Indexed: 01/24/2024]
Abstract
Serine is a metabolite with ever-expanding metabolic and non-metabolic signaling attributes. By providing one‑carbon units for macromolecule biosynthesis and functional modifications, serine and serine metabolism largely impinge on cellular survival and function. Cancer cells frequently have a preference for serine metabolic reprogramming to create a conducive metabolic state for survival and aggressiveness, making intervention of cancer-associated rewiring of serine metabolism a promising therapeutic strategy for cancer treatment. Beyond providing methyl donors for methylation in modulation of innate immunity, serine metabolism generates formyl donors for mitochondrial tRNA formylation which is required for mitochondrial function. Interestingly, fully developed neurons lack the machinery for serine biosynthesis and rely heavily on astrocytic l-serine for production of d-serine to shape synaptic plasticity. Here, we recapitulate recent discoveries that address the medical significance of serine and serine metabolism in malignancies, mitochondrial-associated disorders, and neurodegenerative pathologies. Metabolic control and epigenetic- and posttranslational regulation of serine metabolism are also discussed. Given the metabolic similarities between cancer cells, neurons and germ cells, we further propose the relevance of serine metabolism in testicular homeostasis. Our work provides valuable hints for future investigations that will lead to a deeper understanding of serine and serine metabolism in cellular physiology and pathology.
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Affiliation(s)
- Di Wu
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China
| | - Kejia Zhang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China
| | - Faheem Ahmed Khan
- Research Center for Animal Husbandry, National Research and Innovation Agency, Jakarta Pusat 10340, Indonesia
| | | | - Kaifeng Guan
- School of Advanced Agricultural Sciences, Peking University, Beijing 100871, China.
| | - Fei Sun
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China.
| | - Chunjie Huang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong 226001, China.
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11
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Xiang Y, Song X, Long D. Ferroptosis regulation through Nrf2 and implications for neurodegenerative diseases. Arch Toxicol 2024; 98:579-615. [PMID: 38265475 PMCID: PMC10861688 DOI: 10.1007/s00204-023-03660-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 12/07/2023] [Indexed: 01/25/2024]
Abstract
This article provides an overview of the background knowledge of ferroptosis in the nervous system, as well as the key role of nuclear factor E2-related factor 2 (Nrf2) in regulating ferroptosis. The article takes Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) as the starting point to explore the close association between Nrf2 and ferroptosis, which is of clear and significant importance for understanding the mechanism of neurodegenerative diseases (NDs) based on oxidative stress (OS). Accumulating evidence links ferroptosis to the pathogenesis of NDs. As the disease progresses, damage to the antioxidant system, excessive OS, and altered Nrf2 expression levels, especially the inhibition of ferroptosis by lipid peroxidation inhibitors and adaptive enhancement of Nrf2 signaling, demonstrate the potential clinical significance of Nrf2 in detecting and identifying ferroptosis, as well as targeted therapy for neuronal loss and mitochondrial dysfunction. These findings provide new insights and possibilities for the treatment and prevention of NDs.
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Affiliation(s)
- Yao Xiang
- School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China
| | - Xiaohua Song
- School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China
| | - Dingxin Long
- School of Public Health, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China.
- Hunan Province Key Laboratory of Typical Environmental Pollution and Health Hazards, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China.
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12
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Dinkova-Kostova AT, Hakomäki H, Levonen AL. Electrophilic metabolites targeting the KEAP1/NRF2 partnership. Curr Opin Chem Biol 2024; 78:102425. [PMID: 38241876 DOI: 10.1016/j.cbpa.2024.102425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/03/2024] [Accepted: 01/03/2024] [Indexed: 01/21/2024]
Abstract
Numerous electrophilic metabolites are formed during cellular activity, particularly under conditions of oxidative, inflammatory and metabolic stress. Among them are lipid oxidation and nitration products, and compounds derived from amino acid and central carbon metabolism. Here we focus on one cellular target of electrophiles, the Kelch-like ECH associated protein 1 (KEAP1)/nuclear factor erythroid 2 p45-related factor 2 (NRF2) partnership. Many of these reactive compounds modify C151, C273 and/or C288 within KEAP1. Other types of modifications include S-lactoylation of C273, N-succinylation of K131, and formation of methylimidazole intermolecular crosslink between two KEAP1 monomers. Modified KEAP1 relays the initial signal to transcription factor NRF2 and its downstream targets, the ultimate effectors that provide means for detoxification, adaptation and survival. Thus, by non-enzymatically covalently modifying KEAP1, the electrophilic metabolites discussed here serve as chemical signals connecting metabolism with stress responses.
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Affiliation(s)
- Albena T Dinkova-Kostova
- Jacqui Wood Cancer Centre, Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Dundee, UK; Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Henriikka Hakomäki
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Anna-Liisa Levonen
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
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Napoli M, Deshpande AA, Chakravarti D, Rajapakshe K, Gunaratne PH, Coarfa C, Flores ER. Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses. CANCER RESEARCH COMMUNICATIONS 2024; 4:264-278. [PMID: 38165157 PMCID: PMC10832605 DOI: 10.1158/2767-9764.crc-23-0358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 11/14/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024]
Abstract
The p53 family member TP63 encodes two sets of N-terminal isoforms, TAp63 and ΔNp63 isoforms. They each regulate diverse biological functions in epidermal morphogenesis and in cancer. In the skin, where their activities have been extensively characterized, TAp63 prevents premature aging by regulating the quiescence and genomic stability of stem cells required for wound healing and hair regeneration, while ΔNp63 controls maintenance and terminal differentiation of epidermal basal cells. This functional diversity is surprising given that these isoforms share a high degree of similarity, including an identical sequence for a DNA-binding domain. To understand the mechanisms of the transcriptional programs regulated by each p63 isoform and leading to diverse biological functions, we performed genome-wide analyses using p63 isoform-specific chromatin immunoprecipitation, RNA sequencing, and metabolomics of TAp63-/- and ΔNp63-/- mouse epidermal cells. Our data indicate that TAp63 and ΔNp63 physically and functionally interact with distinct transcription factors for the downstream regulation of their target genes, thus ultimately leading to the regulation of unique transcriptional programs and biological processes. Our findings unveil novel transcriptomes regulated by the p63 isoforms to control diverse biological functions, including the cooperation between TAp63 and NRF2 in the modulation of metabolic pathways and response to oxidative stress providing a mechanistic explanation for the TAp63 knock out phenotypes. SIGNIFICANCE The p63 isoforms, TAp63 and ΔNp63, control epithelial morphogenesis and tumorigenesis through the interaction with distinct transcription factors and the subsequent regulation of unique transcriptional programs.
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Affiliation(s)
- Marco Napoli
- Department of Molecular Oncology, Division of Basic Science, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Avani A. Deshpande
- Department of Molecular Oncology, Division of Basic Science, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | | | - Kimal Rajapakshe
- Sheikh Ahmed Center for Pancreatic Cancer Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
| | | | - Cristian Coarfa
- Department of Molecular and Cellular Biology, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Elsa R. Flores
- Department of Molecular Oncology, Division of Basic Science, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
- Cancer Biology and Evolution Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
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14
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Karagiannis D, Wu W, Li A, Hayashi M, Chen X, Yip M, Mangipudy V, Xu X, Sánchez-Rivera FJ, Soto-Feliciano YM, Ye J, Papagiannakopoulos T, Lu C. Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors. Cell Rep 2024; 43:113629. [PMID: 38165806 PMCID: PMC10853943 DOI: 10.1016/j.celrep.2023.113629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 10/27/2023] [Accepted: 12/12/2023] [Indexed: 01/04/2024] Open
Abstract
The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.
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Affiliation(s)
- Dimitris Karagiannis
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Warren Wu
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Albert Li
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Makiko Hayashi
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Xiao Chen
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Michaela Yip
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Vaibhav Mangipudy
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Xinjing Xu
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Francisco J Sánchez-Rivera
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Yadira M Soto-Feliciano
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
| | - Jiangbin Ye
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Thales Papagiannakopoulos
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter NYU Cancer Center, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Chao Lu
- Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
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15
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Pfefferlé M, Vallelian F. Transcription Factor NRF2 in Shaping Myeloid Cell Differentiation and Function. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1459:159-195. [PMID: 39017844 DOI: 10.1007/978-3-031-62731-6_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/18/2024]
Abstract
NFE2-related factor 2 (NRF2) is a master transcription factor (TF) that coordinates key cellular homeostatic processes including antioxidative responses, autophagy, proteostasis, and metabolism. The emerging evidence underscores its significant role in modulating inflammatory and immune processes. This chapter delves into the role of NRF2 in myeloid cell differentiation and function and its implication in myeloid cell-driven diseases. In macrophages, NRF2 modulates cytokine production, phagocytosis, pathogen clearance, and metabolic adaptations. In dendritic cells (DCs), it affects maturation, cytokine production, and antigen presentation capabilities, while in neutrophils, NRF2 is involved in activation, migration, cytokine production, and NETosis. The discussion extends to how NRF2's regulatory actions pertain to a wide array of diseases, such as sepsis, various infectious diseases, cancer, wound healing, atherosclerosis, hemolytic conditions, pulmonary disorders, hemorrhagic events, and autoimmune diseases. The activation of NRF2 typically reduces inflammation, thereby modifying disease outcomes. This highlights the therapeutic potential of NRF2 modulation in treating myeloid cell-driven pathologies.
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Affiliation(s)
- Marc Pfefferlé
- Department of Internal Medicine, Spital Limmattal, Schlieren, Switzerland
| | - Florence Vallelian
- Department of Internal Medicine, University of Zurich and University Hospital of Zurich, Zurich, Switzerland.
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16
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Hasan A, Khan NA, Uddin S, Khan AQ, Steinhoff M. Deregulated transcription factors in the emerging cancer hallmarks. Semin Cancer Biol 2024; 98:31-50. [PMID: 38123029 DOI: 10.1016/j.semcancer.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/25/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023]
Abstract
Cancer progression is a multifaceted process that entails several stages and demands the persistent expression or activation of transcription factors (TFs) to facilitate growth and survival. TFs are a cluster of proteins with DNA-binding domains that attach to promoter or enhancer DNA strands to start the transcription of genes by collaborating with RNA polymerase and other supporting proteins. They are generally acknowledged as the major regulatory molecules that coordinate biological homeostasis and the appropriate functioning of cellular components, subsequently contributing to human physiology. TFs proteins are crucial for controlling transcription during the embryonic stage and development, and the stability of different cell types depends on how they function in different cell types. The development and progression of cancer cells and tumors might be triggered by any anomaly in transcription factor function. It has long been acknowledged that cancer development is accompanied by the dysregulated activity of TF alterations which might result in faulty gene expression. Recent studies have suggested that dysregulated transcription factors play a major role in developing various human malignancies by altering and rewiring metabolic processes, modifying the immune response, and triggering oncogenic signaling cascades. This review emphasizes the interplay between TFs involved in metabolic and epigenetic reprogramming, evading immune attacks, cellular senescence, and the maintenance of cancer stemness in cancerous cells. The insights presented herein will facilitate the development of innovative therapeutic modalities to tackle the dysregulated transcription factors underlying cancer.
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Affiliation(s)
- Adria Hasan
- Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Lucknow 226026, India; Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow 226026, India
| | - Naushad Ahmad Khan
- Department of Surgery, Trauma and Vascular Surgery Clinical Research, Hamad General Hospital, Doha 3050, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Department of Biosciences, Integral University, Lucknow 226026, India; Animal Research Center, Qatar University, Doha, Qatar; Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
| | - Abdul Q Khan
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar.
| | - Martin Steinhoff
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar; Animal Research Center, Qatar University, Doha, Qatar; Department of Dermatology and Venereology, Rumailah Hospital, Hamad Medical Corporation, Doha 3050, Qatar; Department of Medicine, Weill Cornell Medicine Qatar, Qatar Foundation-Education City, Doha 24144, Qatar; Department of Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; College of Medicine, Qatar University, Doha 2713, Qatar
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17
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Di Giorgio E, Cortolezzis Y, Gualandi N, Agostini F, Rapozzi V, Xodo LE. NRF2 interacts with distal enhancer and inhibits nitric oxide synthase 2 expression in KRAS-driven pancreatic cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119606. [PMID: 37852325 DOI: 10.1016/j.bbamcr.2023.119606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/20/2023]
Abstract
Nitric oxide is a pleiotropic free radical produced by three nitric oxide synthases (NOS1-3), of which inducible NOS2 is involved in tumor initiation and progression. In this study, RNA-seq, ChIP-seq and qRT-PCR experiments combined with bioinformatic analyses showed that NRF2 is a repressor of NOS2 gene by maintaining a distal enhancer located 22 kb downstream of TSS in an inactive state. Deletion of NRF2 leads to activation of the enhancer, which exerts a pioneering function before it is fully activated. Specifically, NRF2 controls the expression of NOS2 in response to intracellular oxidative stress and extracellular oxygen pressure. We found that abrogation of NOS2 expression by siRNAs partially reduced the ability of WT Panc-1 cells to form 3D spheroids, but strongly reduced the formation of 3D spheroids by NRF2-depleted Panc-1 cells. Mechanistically, this effect correlates with the finding that NOS2 and nitric oxide stimulate epithelial-to-mesenchymal transition in NRF2-depleted Panc-1 and MIA PaCa-2 cells. We also found that knockdown of NOS2 leads to blockade of 3D matrigel invasion of NRF2-depleted PDAC cells, demonstrating that a short-circuit in the reciprocal regulation of NOS2 and NRF2 attenuates the malignancy of PDAC cells. In summary, we show for the first time that: (i) NRF2 is a suppressor of NOS2 in pancreatic cancer cells; (ii) NRF2 binds to and inactivates an enhancer located 22 kb downstream of TSS of the NOS2 gene; (iii) activation of NOS2 requires suppression of NRF2; (iv) NOS2 is required for NRF2-depleted Panc-1 cells to maintain their malignancy and invasiveness.
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Affiliation(s)
- Eros Di Giorgio
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy.
| | - Ylenia Cortolezzis
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Nicolò Gualandi
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Francesca Agostini
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Valentina Rapozzi
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Luigi E Xodo
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy.
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18
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Di Giorgio E, Choudhary H, Ferino A, Cortolezzis Y, Dalla E, D’Este F, Comelli M, Rapozzi V, Xodo LE. Suppression of the KRAS- NRF2 axis shifts arginine into the phosphocreatine energy system in pancreatic cancer cells. iScience 2023; 26:108566. [PMID: 38144458 PMCID: PMC10746371 DOI: 10.1016/j.isci.2023.108566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 10/21/2023] [Accepted: 11/21/2023] [Indexed: 12/26/2023] Open
Abstract
In pancreatic ductal adenocarcinomas (PDAC), the KRASG12D-NRF2 axis controls cellular functions such as redox homeostasis and metabolism. Disruption of this axis through suppression of NRF2 leads to profound reprogramming of metabolism. Unbiased transcriptome and metabolome analyses showed that PDAC cells with disrupted KRASG12D-NRF2 signaling (NRF2-/- cells) shift from aerobic glycolysis to metabolic pathways fed by amino acids. Metabolome, RNA-seq and qRT-PCR analyses revealed a blockade of the urea cycle, making NRF2-/- cells dependent on exogenous arginine for survival. Arginine is channeled into anabolic pathways, including the synthesis of phosphocreatine, which generates an energy buffer essential for cell growth. A similar switch was observed in tumor clones that had survived FOLFIRINOX therapy or blockade of KRAS signaling. Inhibition of the creatine pathway with cyclocreatine reduced both ATP and invasion rate in 3D spheroids from NRF2-deficient PDAC cells. Our study provides basis for the rational development of combination therapies for pancreatic cancer.
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Affiliation(s)
- Eros Di Giorgio
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Himanshi Choudhary
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Annalisa Ferino
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Ylenia Cortolezzis
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Emiliano Dalla
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Francesca D’Este
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Marina Comelli
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Valentina Rapozzi
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
| | - Luigi E. Xodo
- Department of Medicine, Laboratory of Biochemistry, P.le Kolbe 4, 33100 Udine, Italy
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19
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Schaer DJ, Schulthess-Lutz N, Baselgia L, Hansen K, Buzzi RM, Humar R, Dürst E, Vallelian F. Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance. J Clin Invest 2023; 134:e174528. [PMID: 38060331 PMCID: PMC10849758 DOI: 10.1172/jci174528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 11/28/2023] [Indexed: 02/02/2024] Open
Abstract
Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in perinecrotic hemorrhagic tumor regions. These cells resembled antiinflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-Seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial-mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFN-γ and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance.
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20
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Vatashchuk MV, Bayliak MM, Hurza VV, Demianchuk OI, Gospodaryov DV, Lushchak VI. Alpha-ketoglutarate partially alleviates effects of high-fat high-fructose diet in mouse muscle. EXCLI JOURNAL 2023; 22:1264-1277. [PMID: 38234967 PMCID: PMC10792174 DOI: 10.17179/excli2023-6608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 11/14/2023] [Indexed: 01/19/2024]
Abstract
Consumption of high-calorie diets leads to excessive accumulation of storage lipids in adipose tissue. Metabolic changes occur not only in adipose tissue but in other tissues, too, such as liver, heart, muscle, and brain. This study aimed to explore the effects of high-fat high-fructose diet (HFFD) alone and in the combination with alpha-ketoglutarate (AKG), a well-known cellular metabolite, on energy metabolism in the skeletal muscle of C57BL/6J mice. Five-month-old male mice were divided into four groups - the control one fed a standard diet (10 % kcal fat), HFFD group fed a high-fat high-fructose diet (45 % kcal fat, 15 % kcal fructose), AKG group fed a standard diet with 1 % sodium AKG in drinking water, and HFFD + AKG group fed HFFD and water with 1 % sodium AKG. The dietary regimens lasted 8 weeks. Mice fed HFFD had higher levels of storage triacylglycerides, lower levels of glycogen, and total water-soluble protein, and higher activities of key glycolytic enzymes, namely hexokinase, phosphofructokinase, and pyruvate kinase, as compared with the control group. The results suggest that muscles of HFFD mice may suffer from lipotoxicity. In HFFD + AKG mice, levels of the metabolites and activities of glycolytic enzymes did not differ from the respective values in the control group, except for the activity of pyruvate kinase, which was significantly lower in HFFD + AKG group compared with the control. Thus, metabolic changes in mouse skeletal muscles, caused by HFFD, were alleviated by AKG, indicating a protective role of AKG regarding lipotoxicity.
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Affiliation(s)
- Myroslava V. Vatashchuk
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., Ivano-Frankivsk, 76018, Ukraine
| | - Maria M. Bayliak
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., Ivano-Frankivsk, 76018, Ukraine
| | - Viktoriia V. Hurza
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., Ivano-Frankivsk, 76018, Ukraine
| | - Oleh I. Demianchuk
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., Ivano-Frankivsk, 76018, Ukraine
| | - Dmytro V. Gospodaryov
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., Ivano-Frankivsk, 76018, Ukraine
| | - Volodymyr I. Lushchak
- Department of Biochemistry and Biotechnology, Vasyl Stefanyk Precarpathian National University, 57 Shevchenko Str., Ivano-Frankivsk, 76018, Ukraine
- Research and Development University, 13a Shota Rustaveli Str., Ivano-Frankivsk, 76018, Ukraine
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21
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Feng R, Liu C, Cui Z, Liu Z, Zhang Y. Sphingosine 1-phosphate combining with S1PR4 promotes regulatory T cell differentiation related to FAO through Nrf2/PPARα. Scand J Immunol 2023; 98:e13322. [PMID: 39007959 DOI: 10.1111/sji.13322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 07/01/2023] [Accepted: 08/02/2023] [Indexed: 07/16/2024]
Abstract
Metabolism and metabolic processes have long been considered to shape the tumour immunosuppressive microenvironment. Recent research has demonstrated that T regulatory cells (Tregs) display high rates of fatty acid oxidation (FAO) and a relatively low rate of glycolysis. Sphingosine 1-phosphate (S1P), which is a G protein signalling activator involved in immune regulation and FAO modulation, has been implicated in Treg differentiation. However, the precise relation between Treg differentiation and S1P remains unclear. In this study, we isolated naïve CD4+ T cells from the spleens of 6-8-week-old BALB/c mice using magnetic bead sorting, which was used in our study for Treg differentiation. S1P stimulation was performed during Treg differentiation. We examined the oxygen consumption and palmitic acid metabolism of the differentiated Tregs and evaluated the expression levels of various proteins, including Nrf2, CPT1A, Glut1, ACC1 and PPARα, through Western blotting. Our results demonstrate that S1P promotes Treg differentiation and enhances FAO, and that the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and peroxisome proliferator-activated receptor α (PPARα) is upregulated. Furthermore, Nrf2 or PPARα knockdown dampened the Treg differentiation and FAO that were promoted by S1P, confirming that S1P can bind with S1PR4 to promote Treg differentiation through the Nrf2/PPARα signalling pathway, which may be related to FAO facilitation.
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Affiliation(s)
- Rui Feng
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Chuang Liu
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Zilin Cui
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Zirong Liu
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Yamin Zhang
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin, China
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22
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Paiboonrungruang C, Xiong Z, Lamson D, Li Y, Bowman B, Chembo J, Huang C, Li J, Livingston EW, Frank JE, Chen V, Li Y, Weissman B, Yuan H, Williams KP, Ben Major M, Chen X. Small molecule screen identifies pyrimethamine as an inhibitor of NRF2-driven esophageal hyperplasia. Redox Biol 2023; 67:102901. [PMID: 37776708 PMCID: PMC10558795 DOI: 10.1016/j.redox.2023.102901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/19/2023] [Accepted: 09/21/2023] [Indexed: 10/02/2023] Open
Abstract
OBJECTIVE NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2high ESCC. DESIGN We performed high-throughput screening of two compound libraries from which hit compounds were further validated in human ESCC cells and a genetically modified mouse model. The mechanism of action of one compound was explored by biochemical assays. RESULTS Using high-throughput screening of two small molecule compound libraries, we identified 11 hit compounds as potential NRF2 inhibitors with minimal cytotoxicity at specified concentrations. We then validated two of these compounds, pyrimethamine and mitoxantrone, by demonstrating their dose- and time-dependent inhibitory effects on the expression of NRF2 and its target genes in two NRF2Mut human ESCC cells (KYSE70 and KYSE180). RNAseq and qPCR confirmed the suppression of global NRF2 signaling by these two compounds. Mechanistically, pyrimethamine reduced NRF2 half-life by promoting NRF2 ubiquitination and degradation in KYSE70 and KYSE180 cells. Expression of an Nrf2E79Q allele in mouse esophageal epithelium (Sox2CreER;LSL-Nrf2E79Q/+) resulted in an NRF2high phenotype, which included squamous hyperplasia, hyperkeratinization, and hyperactive glycolysis. Treatment with pyrimethamine (30 mg/kg/day, p.o.) suppressed the NRF2high esophageal phenotype with no observed toxicity. CONCLUSION We have identified and validated pyrimethamine as an NRF2 inhibitor that may be rapidly tested in the clinic for NRF2high ESCC.
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Affiliation(s)
- Chorlada Paiboonrungruang
- Coriell Institute for Medical Research, Camden, NJ, 08103, USA; Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, 27707, USA
| | - Zhaohui Xiong
- Coriell Institute for Medical Research, Camden, NJ, 08103, USA; Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, 27707, USA
| | - David Lamson
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC, 27707, USA
| | - Yahui Li
- Coriell Institute for Medical Research, Camden, NJ, 08103, USA; Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, 27707, USA
| | - Brittany Bowman
- Department of Cell Biology and Physiology, Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Julius Chembo
- Department of Cell Biology and Physiology, Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO, 63110, USA
| | - Caizhi Huang
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, 27707, USA
| | - Jianying Li
- Euclados Bioinformatics Solutions, Cary, NC, 27519, USA
| | - Eric W Livingston
- Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, 277599, USA
| | - Jon E Frank
- Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, 277599, USA
| | - Vivian Chen
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, 27707, USA
| | - Yong Li
- Department of Thoracic Surgery, National Cancer Center, Cancer Hospital of Chinese Academy of Medical Sciences, Beijing, 100021, China
| | - Bernard Weissman
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 277599, USA
| | - Hong Yuan
- Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, 277599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 277599, USA; Department of Radiology, University of North Carolina, Chapel Hill, NC, 277599, USA
| | - Kevin P Williams
- Department of Pharmaceutical Sciences, Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC, 27707, USA.
| | - M Ben Major
- Department of Cell Biology and Physiology, Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO, 63110, USA.
| | - Xiaoxin Chen
- Coriell Institute for Medical Research, Camden, NJ, 08103, USA; Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, 27707, USA; Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ, 08103, USA; MD Anderson Cancer Center at Cooper, Camden, NJ, 08103, USA; Cooper Medical School of Rowan University, Camden, NJ, 08103, USA.
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23
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Tang YC, Chuang YJ, Chang HH, Juang SH, Yen GC, Chang JY, Kuo CC. How to deal with frenemy NRF2: Targeting NRF2 for chemoprevention and cancer therapy. J Food Drug Anal 2023; 31:387-407. [PMID: 39666284 PMCID: PMC10629913 DOI: 10.38212/2224-6614.3463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/09/2023] [Indexed: 12/13/2024] Open
Abstract
Induction of antioxidant proteins and phase 2 detoxifying enzymes that neutralize reactive electrophiles are important mechanisms for protection against carcinogenesis. Normal cells provide multifaceted pathways to tightly control NF-E2-related factor 2 (NRF2)-mediated gene expression in response to an assault by a range of endogenous and exogenous oncogenic molecules. Transient activation of NRF2 by its activators is able to induce ARE-mediated cytoprotective proteins which are essential for protection against various toxic and oxidative damages, and NRF2 activators thereby have efficacy in cancer chemoprevention. Because NRF2 has a cytoprotective function, it can protect normal cells from carcinogens like an angel, but when the protective effect acts on cancer cells, it will give rise to invincible cancer cells and play a devilish role in tumor progression. Indeed, aberrant activation of NRF2 has been found in a variety of cancers that create a favorable environment for the proliferation and survival of cancer cells and leads to drug resistance, ultimately leading to the poor clinical prognosis of patients. Therefore, pharmacological inhibition of NRF2 signaling has emerged as a promising approach for cancer therapy. This review aims to compile the regulatory mechanisms of NRF2 and its double-edged role in cancer. In addition, we also summarize the research progress of NRF2 modulators, especially phytochemicals, in chemoprevention and cancer therapy.
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Affiliation(s)
- Ya-Chu Tang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli,
Taiwan
| | - Yung-Jen Chuang
- School of Medicine, National Tsing Hua University, Hsinchu,
Taiwan
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu,
Taiwan
| | - Hsin-Huei Chang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli,
Taiwan
| | - Shin-Hun Juang
- School of Pharmacy, China Medical University, Taichung,
Taiwan
| | - Gow-Chin Yen
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung,
Taiwan
| | - Jang-Yang Chang
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli,
Taiwan
- Taipei Cancer Center, Taipei Medical University Hospital, Taipei,
Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei,
Taiwan
| | - Ching-Chuan Kuo
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli,
Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung,
Taiwan
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24
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Karagiannis D, Wu W, Li A, Hayashi M, Chen X, Yip M, Mangipudy V, Xu X, Sánchez-Rivera FJ, Soto-Feliciano YM, Ye J, Papagiannakopoulos T, Lu C. Metabolic Reprogramming by Histone Deacetylase Inhibition Selectively Targets NRF2-activated tumors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.24.538118. [PMID: 37162970 PMCID: PMC10168258 DOI: 10.1101/2023.04.24.538118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Interplay between metabolism and chromatin signaling have been implicated in cancer initiation and progression. However, whether and how metabolic reprogramming in tumors generates specific epigenetic vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor mutations that cause aberrant activation of the NRF2 antioxidant pathway and drive aggressive and chemo-resistant disease. We performed a chromatin-focused CRISPR screen and report that NRF2 activation sensitized LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDAC). This association was consistently observed across cultured cells, syngeneic mouse models and patient-derived xenografts. HDAC inhibition causes widespread increases in histone H4 acetylation (H4ac) at intergenic regions, but also drives re-targeting of H4ac reader protein BRD4 away from promoters with high H4ac levels and transcriptional downregulation of corresponding genes. Integrative epigenomic, transcriptomic and metabolomic analysis demonstrates that these chromatin changes are associated with reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest that metabolic alterations such as NRF2 activation could serve as biomarkers for effective repurposing of HDAC inhibitors to treat solid tumors.
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25
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Rajan S, Tryphena KP, Khan S, Vora L, Srivastava S, Singh SB, Khatri DK. Understanding the involvement of innate immunity and the Nrf2-NLRP3 axis on mitochondrial health in Parkinson's disease. Ageing Res Rev 2023; 87:101915. [PMID: 36963313 DOI: 10.1016/j.arr.2023.101915] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 02/01/2023] [Accepted: 03/19/2023] [Indexed: 03/26/2023]
Abstract
Parkinson's disease (PD), a multifactorial movement disorder, is interlinked with numerous molecular pathways, including neuroinflammation, which is a critical factor in the development and progression of PD. Microglia play a central role in driving neuroinflammation through activation and overexpression of the M1 phenotype, which has a significant impact on mitochondria. Multiple regulators converge together, and among these, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes have been implicated in transmitting inflammatory and deleterious components to the mitochondria. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates the NLRP3 inflammasome and acts as the saviour of the mitochondria. Together, the NLRP3-Nrf2 axis functions in regulating mitochondrial function in the case of PD. It regulates fundamental processes such as oxidative stress, mitochondrial respiratory function, and mitochondrial dynamics. In this review, we discuss the contributions that a variety of miRNAs make to the regulation of the NLRP3 inflammasome and Nrf2, which can be used to target this important axis and contribute to the preservation of mitochondrial integrity. This axis may prove to be a crucial target for extending the lives of Parkinson's patients by deferring neuroinflammatory damage to mitochondria.
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Affiliation(s)
- Shruti Rajan
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India
| | - Kamatham Pushpa Tryphena
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India
| | - Sabiya Khan
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India
| | - Lalitkumar Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
| | - Saurabh Srivastava
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India.
| | - Shashi Bala Singh
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India
| | - Dharmendra Kumar Khatri
- Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, Telangana 500037, India.
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26
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Wang R, Liang L, Matsumoto M, Iwata K, Umemura A, He F. Reactive Oxygen Species and NRF2 Signaling, Friends or Foes in Cancer? Biomolecules 2023; 13:biom13020353. [PMID: 36830722 PMCID: PMC9953152 DOI: 10.3390/biom13020353] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/03/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
The imbalance between reactive oxygen species (ROS) production and clearance causes oxidative stress and ROS, which play a central role in regulating cell and tissue physiology and pathology. Contingent upon concentration, ROS influence cancer development in contradictory ways, either stimulating cancer survival and growth or causing cell death. Cells developed evolutionarily conserved programs to sense and adapt redox the fluctuations to regulate ROS as either signaling molecules or toxic insults. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2)-KEAP1 system is the master regulator of cellular redox and metabolic homeostasis. NRF2 has Janus-like roles in carcinogenesis and cancer development. Short-term NRF2 activation suppresses tissue injury, inflammation, and cancer initiation. However, cancer cells often exhibit constitutive NRF2 activation due to genetic mutations or oncogenic signaling, conferring advantages for cancer cells' survival and growth. Emerging evidence suggests that NRF2 hyperactivation, as an adaptive cancer phenotype under stressful tumor environments, regulates all hallmarks of cancer. In this review, we summarized the source of ROS, regulation of ROS signaling, and cellular sensors for ROS and oxygen (O2), we reviewed recent progress on the regulation of ROS generation and NRF2 signaling with a focus on the new functions of NRF2 in cancer development that reach beyond what we originally envisioned, including regulation of cancer metabolism, autophagy, macropinocytosis, unfolded protein response, proteostasis, and circadian rhythm, which, together with anti-oxidant and drug detoxification enzymes, contributes to cancer development, metastasis, and anticancer therapy resistance.
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Affiliation(s)
- Ruolei Wang
- The Center for Cancer Research, Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lirong Liang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China
| | - Misaki Matsumoto
- Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Kazumi Iwata
- Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Atsushi Umemura
- Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
- Correspondence: (A.U.); (F.H.); Tel.: +75-251-5332 (A.U.); +86-21-5132-2501 (F.H.)
| | - Feng He
- The Center for Cancer Research, Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Correspondence: (A.U.); (F.H.); Tel.: +75-251-5332 (A.U.); +86-21-5132-2501 (F.H.)
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27
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Ooki A, Osumi H, Chin K, Watanabe M, Yamaguchi K. Potent molecular-targeted therapies for advanced esophageal squamous cell carcinoma. Ther Adv Med Oncol 2023; 15:17588359221138377. [PMID: 36872946 PMCID: PMC9978325 DOI: 10.1177/17588359221138377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 10/21/2022] [Indexed: 01/15/2023] Open
Abstract
Esophageal cancer (EC) remains a public health concern with a high mortality and disease burden worldwide. Esophageal squamous cell carcinoma (ESCC) is a predominant histological subtype of EC that has unique etiology, molecular profiles, and clinicopathological features. Although systemic chemotherapy, including cytotoxic agents and immune checkpoint inhibitors, is the main therapeutic option for recurrent or metastatic ESCC patients, the clinical benefits are limited with poor prognosis. Personalized molecular-targeted therapies have been hampered due to the lack of robust treatment efficacy in clinical trials. Therefore, there is an urgent need to develop effective therapeutic strategies. In this review, we summarize the molecular profiles of ESCC based on the findings of pivotal comprehensive molecular analyses, highlighting potent therapeutic targets for establishing future precision medicine for ESCC patients, with the most recent results of clinical trials.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy,
Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31
Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy,
Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo,
Japan
| | - Keisho Chin
- Department of Gastroenterological Chemotherapy,
Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo,
Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery,
Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo,
Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy,
Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo,
Japan
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28
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Testa U, Castelli G, Pelosi E. The Molecular Characterization of Genetic Abnormalities in Esophageal Squamous Cell Carcinoma May Foster the Development of Targeted Therapies. Curr Oncol 2023; 30:610-640. [PMID: 36661697 PMCID: PMC9858483 DOI: 10.3390/curroncol30010048] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/24/2022] [Accepted: 12/29/2022] [Indexed: 01/06/2023] Open
Abstract
Esophageal cancer is among the most common tumors in the world and is associated with poor outcomes, with a 5-year survival rate of about 10-20%. Two main histological subtypes are observed: esophageal squamous cell carcinoma (ESCC), more frequent among Asian populations, and esophageal adenocarcinoma (EAC), the predominant type in Western populations. The development of molecular analysis techniques has led to the definition of the molecular alterations observed in ESCC, consistently differing from those observed in EAC. The genetic alterations observed are complex and heterogeneous and involve gene mutations, gene deletions and gene amplifications. However, despite the consistent progress in the definition of the molecular basis of ESCC, precision oncology for these patients is still virtually absent. The recent identification of molecular subtypes of ESCC with clinical relevance may foster the development of new therapeutic strategies. It is estimated that about 40% of the genetic alterations observed in ESCC are actionable. Furthermore, the recent introduction of solid tumor immunotherapy with immune checkpoint inhibitors (ICIs) showed that a minority of ESCC patients are responsive, and the administration of ICIs, in combination with standard chemotherapy, significantly improves overall survival over chemotherapy in ESCC patients with advanced disease.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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29
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Xu K, Ma J, Hall SRR, Peng RW, Yang H, Yao F. Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks. Theranostics 2023; 13:704-723. [PMID: 36632216 PMCID: PMC9830441 DOI: 10.7150/thno.80184] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/14/2022] [Indexed: 01/06/2023] Open
Abstract
The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.
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Affiliation(s)
- Ke Xu
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China
| | - Jie Ma
- Department of Thoracic Surgery, Anhui Chest Hospital, Hefei, 230000, China
| | - Sean R. R. Hall
- Wyss Institute for Biologically Inspired Engineering, Harvard University; Boston, MA 02115, USA
| | - Ren-Wang Peng
- Division of General Thoracic Surgery, Department of BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern; Bern, 3010, Switzerland
| | - Haitang Yang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.,✉ Corresponding author: Haitang Yang (, +86 18217015189), Feng Yao (, +86 13636354837), Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University. West Huaihai 241, 200030, Shanghai, People's Republic of China
| | - Feng Yao
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China
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30
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Dodson M, Shakya A, Anandhan A, Chen J, Garcia JG, Zhang DD. NRF2 and Diabetes: The Good, the Bad, and the Complex. Diabetes 2022; 71:2463-2476. [PMID: 36409792 PMCID: PMC9750950 DOI: 10.2337/db22-0623] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 09/06/2022] [Indexed: 11/22/2022]
Abstract
Despite decades of scientific effort, diabetes continues to represent an incredibly complex and difficult disease to treat. This is due in large part to the multifactorial nature of disease onset and progression and the multiple organ systems affected. An increasing body of scientific evidence indicates that a key mediator of diabetes progression is NRF2, a critical transcription factor that regulates redox, protein, and metabolic homeostasis. Importantly, while experimental studies have confirmed the critical nature of proper NRF2 function in preventing the onset of diabetic outcomes, we have only just begun to scratch the surface of understanding the mechanisms by which NRF2 modulates diabetes progression, particularly across different causative contexts. One reason for this is the contradictory nature of the current literature, which can often be accredited to model discrepancies, as well as whether NRF2 is activated in an acute or chronic manner. Furthermore, despite therapeutic promise, there are no current NRF2 activators in clinical trials for the treatment of patients with diabetes. In this review, we briefly introduce the transcriptional programs regulated by NRF2 as well as how NRF2 itself is regulated. We also review the current literature regarding NRF2 modulation of diabetic phenotypes across the different diabetes subtypes, including a brief discussion of contradictory results, as well as what is needed to progress the NRF2 diabetes field forward.
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Affiliation(s)
- Matthew Dodson
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
| | - Aryatara Shakya
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
| | - Annadurai Anandhan
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
| | - Jinjing Chen
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
| | - Joe G.N. Garcia
- Department of Medicine, University of Arizona Health Sciences, University of Arizona, Tucson, AZ
| | - Donna D. Zhang
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ
- Arizona Cancer Center, University of Arizona, Tucson, AZ
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31
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Kant R, Manne RK, Anas M, Penugurti V, Chen T, Pan BS, Hsu CC, Lin HK. Deregulated transcription factors in cancer cell metabolisms and reprogramming. Semin Cancer Biol 2022; 86:1158-1174. [PMID: 36244530 PMCID: PMC11220368 DOI: 10.1016/j.semcancer.2022.10.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 09/10/2022] [Accepted: 10/11/2022] [Indexed: 01/27/2023]
Abstract
Metabolic reprogramming is an important cancer hallmark that plays a key role in cancer malignancies and therapy resistance. Cancer cells reprogram the metabolic pathways to generate not only energy and building blocks but also produce numerous key signaling metabolites to impact signaling and epigenetic/transcriptional regulation for cancer cell proliferation and survival. A deeper understanding of the mechanisms by which metabolic reprogramming is regulated in cancer may provide potential new strategies for cancer targeting. Recent studies suggest that deregulated transcription factors have been observed in various human cancers and significantly impact metabolism and signaling in cancer. In this review, we highlight the key transcription factors that are involved in metabolic control, dissect the crosstalk between signaling and transcription factors in metabolic reprogramming, and offer therapeutic strategies targeting deregulated transcription factors for cancer treatment.
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Affiliation(s)
- Rajni Kant
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27101, USA
| | - Rajesh Kumar Manne
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27101, USA
| | - Mohammad Anas
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27101, USA
| | - Vasudevarao Penugurti
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27101, USA
| | - Tingjin Chen
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27101, USA
| | - Bo-Syong Pan
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27101, USA
| | - Che-Chia Hsu
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27101, USA
| | - Hui-Kuan Lin
- Department of Cancer Biology, Wake Forest Baptist Medical Center, Wake Forest University, Winston-Salem, NC 27101, USA.
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32
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The KEAP1-NRF2 System and Esophageal Cancer. Cancers (Basel) 2022; 14:cancers14194702. [PMID: 36230622 PMCID: PMC9564177 DOI: 10.3390/cancers14194702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 09/24/2022] [Accepted: 09/24/2022] [Indexed: 12/18/2022] Open
Abstract
NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that regulates the expression of many cytoprotective genes. NRF2 activation is mainly regulated by KEAP1 (kelch-like ECH-associated protein 1) through ubiquitination and proteasome degradation. Esophageal cancer is classified histologically into two major types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). ESCC harbors more genetic alterations in the KEAP-NRF2 system than EAC does, which results in NRF2 activation in these cancers. NRF2-addicted ESCC exhibits increased malignancy and acquisition of resistance to chemoradiotherapy. Therefore, it has been recognized that the development of drugs targeting the KEAP1-NRF2 system based on the molecular dissection of NRF2 function is important and urgent for the treatment of ESCC, along with efficient clinical screening for NRF2-addicted ESCC patients. Recently, the fate of NRF2-activated cells in esophageal tissues, which was under the influence of strong cell competition, and its relationship to the pathogenesis of ESCC, was clarified. In this review, we will summarize the current knowledge of the KEAP1-NRF2 system and the treatment of ESCC. We propose three main strategies for the treatment of NRF2-addicted cancer: (1) NRF2 inhibitors, (2) synthetic lethal drugs for NRF2-addicted cancers, and (3) NRF2 inducers of the host defense system.
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33
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Manda G, Milanesi E, Genc S, Niculite CM, Neagoe IV, Tastan B, Dragnea EM, Cuadrado A. Pros and cons of NRF2 activation as adjunctive therapy in rheumatoid arthritis. Free Radic Biol Med 2022; 190:179-201. [PMID: 35964840 DOI: 10.1016/j.freeradbiomed.2022.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/02/2022] [Accepted: 08/08/2022] [Indexed: 10/15/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease with an important inflammatory component accompanied by deregulated redox-dependent signaling pathways that are feeding back into inflammation. In this context, we bring into focus the transcription factor NRF2, a master redox regulator that exerts exquisite antioxidant and anti-inflammatory effects. The review does not intend to be exhaustive, but to point out arguments sustaining the rationale for applying an NRF2-directed co-treatment in RA as well as its potential limitations. The involvement of NRF2 in RA is emphasized through an analysis of publicly available transcriptomic data on NRF2 target genes and the findings from NRF2-knockout mice. The impact of NRF2 on concurrent pathologic mechanisms in RA is explained by its crosstalk with major redox-sensitive inflammatory and cell death-related pathways, in the context of the increased survival of pathologic cells in RA. The proposed adjunctive therapy targeted to NRF2 is further sustained by the existence of promising NRF2 activators that are in various stages of drug development. The interference of NRF2 with conventional anti-rheumatic therapies is discussed, including the cytoprotective effects of NRF2 for alleviating drug toxicity. From another perspective, the review presents how NRF2 activation would be decreasing the efficacy of synthetic anti-rheumatic drugs by increasing drug efflux. Future perspectives regarding pharmacologic NRF2 activation in RA are finally proposed.
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Affiliation(s)
- Gina Manda
- Radiobiology Laboratory, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Elena Milanesi
- Radiobiology Laboratory, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Sermin Genc
- Neurodegeneration and Neuroprotection Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey; Department of Neuroscience, Health Science Institute, Dokuz Eylul University, Izmir, Turkey
| | - Cristina Mariana Niculite
- Radiobiology Laboratory, Victor Babes National Institute of Pathology, Bucharest, Romania; Department of Cellular and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Ionela Victoria Neagoe
- Radiobiology Laboratory, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Bora Tastan
- Neurodegeneration and Neuroprotection Laboratory, Izmir Biomedicine and Genome Center, Izmir, Turkey; Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey
| | - Elena Mihaela Dragnea
- Radiobiology Laboratory, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Antonio Cuadrado
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
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Esteras N, Abramov AY. Nrf2 as a regulator of mitochondrial function: Energy metabolism and beyond. Free Radic Biol Med 2022; 189:136-153. [PMID: 35918014 DOI: 10.1016/j.freeradbiomed.2022.07.013] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/20/2022] [Accepted: 07/19/2022] [Indexed: 12/14/2022]
Abstract
Mitochondria are unique and essential organelles that mediate many vital cellular processes including energy metabolism and cell death. The transcription factor Nrf2 (NF-E2 p45-related factor 2) has emerged in the last few years as an important modulator of multiple aspects of mitochondrial function. Well-known for controlling cellular redox homeostasis, the cytoprotective effects of Nrf2 extend beyond its ability to regulate a diverse network of antioxidant and detoxification enzymes. Here, we review the role of Nrf2 in the regulation of mitochondrial function and structure. We focus on Nrf2 involvement in promoting mitochondrial quality control and regulation of basic aspects of mitochondrial function, including energy production, reactive oxygen species generation, calcium signalling, and cell death induction. Given the importance of mitochondria in the development of multiple diseases, these findings reinforce the pharmacological activation of Nrf2 as an attractive strategy to counteract mitochondrial dysfunction.
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Affiliation(s)
- Noemí Esteras
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, UK.
| | - Andrey Y Abramov
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, UK.
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35
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Heurtaux T, Bouvier DS, Benani A, Helgueta Romero S, Frauenknecht KBM, Mittelbronn M, Sinkkonen L. Normal and Pathological NRF2 Signalling in the Central Nervous System. Antioxidants (Basel) 2022; 11:1426. [PMID: 35892629 PMCID: PMC9394413 DOI: 10.3390/antiox11081426] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 11/17/2022] Open
Abstract
The nuclear factor erythroid 2-related factor 2 (NRF2) was originally described as a master regulator of antioxidant cellular response, but in the time since, numerous important biological functions linked to cell survival, cellular detoxification, metabolism, autophagy, proteostasis, inflammation, immunity, and differentiation have been attributed to this pleiotropic transcription factor that regulates hundreds of genes. After 40 years of in-depth research and key discoveries, NRF2 is now at the center of a vast regulatory network, revealing NRF2 signalling as increasingly complex. It is widely recognized that reactive oxygen species (ROS) play a key role in human physiological and pathological processes such as ageing, obesity, diabetes, cancer, and neurodegenerative diseases. The high oxygen consumption associated with high levels of free iron and oxidizable unsaturated lipids make the brain particularly vulnerable to oxidative stress. A good stability of NRF2 activity is thus crucial to maintain the redox balance and therefore brain homeostasis. In this review, we have gathered recent data about the contribution of the NRF2 pathway in the healthy brain as well as during metabolic diseases, cancer, ageing, and ageing-related neurodegenerative diseases. We also discuss promising therapeutic strategies and the need for better understanding of cell-type-specific functions of NRF2 in these different fields.
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Affiliation(s)
- Tony Heurtaux
- Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 4367 Belvaux, Luxembourg; (S.H.R.); (M.M.); (L.S.)
- Luxembourg Center of Neuropathology (LCNP), 3555 Dudelange, Luxembourg; (D.S.B.); (K.B.M.F.)
| | - David S. Bouvier
- Luxembourg Center of Neuropathology (LCNP), 3555 Dudelange, Luxembourg; (D.S.B.); (K.B.M.F.)
- National Center of Pathology (NCP), Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg
- Luxembourg Centre of Systems Biomedicine (LCSB), University of Luxembourg, 4367 Belvaux, Luxembourg
| | - Alexandre Benani
- Centre des Sciences du Goût et de l’Alimentation, AgroSup Dijon, CNRS, INRAE, Université Bourgogne Franche-Comté, 21000 Dijon, France;
| | - Sergio Helgueta Romero
- Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 4367 Belvaux, Luxembourg; (S.H.R.); (M.M.); (L.S.)
- Luxembourg Center of Neuropathology (LCNP), 3555 Dudelange, Luxembourg; (D.S.B.); (K.B.M.F.)
| | - Katrin B. M. Frauenknecht
- Luxembourg Center of Neuropathology (LCNP), 3555 Dudelange, Luxembourg; (D.S.B.); (K.B.M.F.)
- National Center of Pathology (NCP), Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg
| | - Michel Mittelbronn
- Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 4367 Belvaux, Luxembourg; (S.H.R.); (M.M.); (L.S.)
- Luxembourg Center of Neuropathology (LCNP), 3555 Dudelange, Luxembourg; (D.S.B.); (K.B.M.F.)
- National Center of Pathology (NCP), Laboratoire National de Santé (LNS), 3555 Dudelange, Luxembourg
- Luxembourg Centre of Systems Biomedicine (LCSB), University of Luxembourg, 4367 Belvaux, Luxembourg
- Luxembourg Institute of Health (LIH), 1526 Luxembourg, Luxembourg
| | - Lasse Sinkkonen
- Department of Life Sciences and Medicine (DLSM), University of Luxembourg, 4367 Belvaux, Luxembourg; (S.H.R.); (M.M.); (L.S.)
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The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation In Vivo. Mol Cell Biol 2022; 42:e0056321. [PMID: 35674451 DOI: 10.1128/mcb.00563-21] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Nrf2 activates cytoprotective gene expression, and Nrf2 activity is regulated through at least two protein degradation pathways: the Keap1-mediated and β-TrCP-mediated pathways. To address the relative contributions of these pathways, we generated knock-in mouse lines expressing an Nrf2SA mutant that harbored two substitution mutations of serine residues interacting with β-TrCP. The homozygous (Nrf2SA/SA) mice grew normally, with Nrf2 levels comparable to those of wild-type (WT) mice under unstressed conditions. However, when Keap1 activity was suppressed, high levels of Nrf2 accumulated in Nrf2SA/SA macrophages compared with that in WT macrophages. We crossed Nrf2SA/SA mice with mice in which Keap1 was knocked down to two different levels. We found that the Nrf2SA/SA mutation induced higher Nrf2 activity when the Keap1 level was strongly reduced, and these mice showed severe growth retardation. However, activation and growth retardation were not evident when Keap1 was moderately suppressed. These increases in Nrf2 activity induced by the Nrf2SA mutation caused severe hyperplasia and hyperkeratosis in the esophageal epithelium but did not cause abnormalities in the other tissues/organs examined. These results indicate that the β-TrCP-mediated pathway cooperates with the Keap1-mediated pathway to regulate Nrf2 activity, which is apparent when the Keap1-mediated pathway is profoundly suppressed.
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Niu ZS, Wang WH. Circular RNAs in hepatocellular carcinoma: Recent advances. World J Gastrointest Oncol 2022; 14:1067-1085. [PMID: 35949213 PMCID: PMC9244981 DOI: 10.4251/wjgo.v14.i6.1067] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/22/2021] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Circular RNAs (circRNAs) have covalently closed loop structures at both ends, exhibiting characteristics dissimilar to those of linear RNAs. Emerging evidence suggests that aberrantly expressed circRNAs play crucial roles in hepatocellular carcinoma (HCC) by affecting the proliferation, apoptosis and invasive capacity of HCC cells. Certain circRNAs may be used as biomarkers to diagnose and predict the prognosis of HCC. Therefore, circRNAs are expected to become novel biomarkers and therapeutic targets for HCC. Herein, we briefly review the characteristics and biological functions of circRNAs, focusing on their roles in HCC to provide new insights for the early diagnosis and targeted therapy of HCC.
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Affiliation(s)
- Zhao-Shan Niu
- Laboratory of Micromorphology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Wen-Hong Wang
- Department of Pathology, School of Basic Medicine, Qingdao University, Qingdao 266071, Shandong Province, China
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38
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Kadian LK, Arora M, Prasad CP, Pramanik R, Chauhan SS. Signaling pathways and their potential therapeutic utility in esophageal squamous cell carcinoma. Clin Transl Oncol 2022; 24:1014-1032. [PMID: 34990001 DOI: 10.1007/s12094-021-02763-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 12/16/2021] [Indexed: 12/12/2022]
Abstract
Esophageal cancer is a complex gastrointestinal malignancy with an extremely poor outcome. Approximately 80% of cases of this malignancy in Asian countries including India are of squamous cell origin, termed Esophageal Squamous Cell Carcinoma (ESCC).The five-year survival rate in ESCC patients is less than 20%. Neo-adjuvant chemo-radiotherapy (NACRT) followed by surgical resection remains the major therapeutic strategy for patients with operable ESCC. However, resistance to NACRT and local recurrence after initial treatment are the leading cause of dismal outcomes in these patients. Therefore, an alternative strategy to promote response to the therapy and reduce the post-operative disease recurrence is highly needed. At the molecular level, wide variations have been observed in tumor characteristics among different populations, nevertheless, several common molecular features have been identified which orchestrate disease progression and clinical outcome in the malignancy. Therefore, determination of candidate molecular pathways for targeted therapy remains the mainstream idea of focus in ESCC research. In this review, we have discussed the key signaling pathways associated with ESCC, i.e., Notch, Wnt, and Nrf2 pathways, and their crosstalk during disease progression. We further discuss the recent developments of novel agents to target these pathways in the context of targeted cancer therapy. In-depth research of the signaling pathways, gene signatures, and a combinatorial approach may help in discovering targeted therapy for ESCC.
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Affiliation(s)
- L K Kadian
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - M Arora
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - C P Prasad
- Department of Medical Oncology (Lab), Dr. B. R. Ambedkar-IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - R Pramanik
- Department of Medical Oncology, Dr. B. R. Ambedkar-IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - S S Chauhan
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India.
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Baumel-Alterzon S, Katz LS, Brill G, Jean-Pierre C, Li Y, Tse I, Biswal S, Garcia-Ocaña A, Scott DK. Nrf2 Regulates β-Cell Mass by Suppressing β-Cell Death and Promoting β-Cell Proliferation. Diabetes 2022; 71:989-1011. [PMID: 35192689 PMCID: PMC9044139 DOI: 10.2337/db21-0581] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 02/15/2022] [Indexed: 01/05/2023]
Abstract
Finding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here, we generated β-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects β-cell survival, proliferation, and mass. Depletion of Nrf2 in β-cells results in decreased glucose-stimulated β-cell proliferation ex vivo and decreased adaptive β-cell proliferation and β-cell mass expansion after a high-fat diet in vivo. Nrf2 protects β-cells from apoptosis after a high-fat diet. Nrf2 loss of function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell-specific manner increases β-cell proliferation and mass and improves glucose tolerance. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with bardoxolone methyl, an Nrf2 activator, display increased β-cell proliferation. Thus, by managing reactive oxygen species levels, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding and protecting β-cell mass in diabetes.
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Affiliation(s)
- Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Liora S. Katz
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Gabriel Brill
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Clairete Jean-Pierre
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Yansui Li
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Isabelle Tse
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Shyam Biswal
- Department of Environmental Health and Engineering, Johns Hopkins University, Baltimore, MD
| | - Adolfo Garcia-Ocaña
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Donald K. Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
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40
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Impact of Advanced Glycation End products (AGEs) and its receptor (RAGE) on cancer metabolic signaling pathways and its progression. Glycoconj J 2022; 38:717-734. [PMID: 35064413 DOI: 10.1007/s10719-021-10031-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/26/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023]
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41
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Paiboonrungruang C, Simpson E, Xiong Z, Huang C, Li J, Li Y, Chen X. Development of targeted therapy of NRF2 high esophageal squamous cell carcinoma. Cell Signal 2021; 86:110105. [PMID: 34358647 PMCID: PMC8403639 DOI: 10.1016/j.cellsig.2021.110105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 02/07/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a deadly disease and one of the most aggressive cancers of the gastrointestinal tract. As a master transcription factor regulating the stress response, NRF2 is often mutated and becomes hyperactive, and thus causes chemo-radioresistance and poor survival in human ESCC. There is a great need to develop NRF2 inhibitors for targeted therapy of NRF2high ESCC. In this review, we mainly focus on three aspects, NRF2 inhibitors and their mechanisms of action, screening novel drug targets, and evaluation of NRF2 activity in the esophagus. A research strategy has been proposed to develop NRF2 inhibitors using human ESCC cells and mouse models.
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Affiliation(s)
- Chorlada Paiboonrungruang
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707, USA
| | - Emily Simpson
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707, USA
| | - Zhaohui Xiong
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707, USA
| | - Caizhi Huang
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC 27607, USA
| | - Jianying Li
- Euclados Bioinformatics Solutions, Cary, NC 27519, USA
| | - Yahui Li
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707, USA
| | - Xiaoxin Chen
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707, USA; Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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42
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Vyas A, Harbison RA, Faden DL, Kubik M, Palmer D, Zhang Q, Osmanbeyoglu HU, Kiselyov K, Méndez E, Duvvuri U. Recurrent Human Papillomavirus-Related Head and Neck Cancer Undergoes Metabolic Reprogramming and Is Driven by Oxidative Phosphorylation. Clin Cancer Res 2021; 27:6250-6264. [PMID: 34407971 DOI: 10.1158/1078-0432.ccr-20-4789] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 05/10/2021] [Accepted: 08/03/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Human papillomavirus (HPV) infection drives the development of some head and neck squamous cell carcinomas (HNSCC). This disease is rapidly increasing in incidence worldwide. Although these tumors are sensitive to treatment, approximately 10% of patients fail therapy. However, the mechanisms that underlie treatment failure remain unclear. EXPERIMENTAL DESIGN We performed RNA sequencing (RNA-seq) on tissues from matched primary- (pHNSCC) and metachronous-recurrent cancers (rHNSCC) to identify transcriptional differences to gain mechanistic insight into the evolutionary adaptations of metachronous-recurrent tumors. We used HPV-related HNSCC cells lines to investigate the effect of (i) NRF2 overexpression on growth in vitro and in vivo, (ii) oxidative phosphorylation (OXPHOS) inhibition using IACS-010759 on NRF2-dependent cells, and (iii) combination of cisplatin and OXPHOS inhibition. RESULTS The OXPHOS pathway is enriched in recurrent HPV-associated HNSCC and may contribute to treatment failure. NRF2-enriched HNSCC samples from The Cancer Genome Atlas (TCGA) with enrichment in OXPHOS, fatty-acid metabolism, Myc, Mtor, reactive oxygen species (ROS), and glycolytic signaling networks exhibited worse survival. HPV-positive HNSCC cells demonstrated sensitivity to the OXPHOS inhibitor, in a NRF2-dependent manner. Further, using murine xenograft models, we identified NRF2 as a driver of tumor growth. Mechanistically, NRF2 drives ROS and mitochondrial respiration, and NRF2 is a critical regulator of redox homeostasis that can be crippled by disruption of OXPHOS. NRF2 also mediated cisplatin sensitivity in endogenously overexpressing primary HPV-related HNSCC cells. CONCLUSIONS These results unveil a paradigm-shifting translational target harnessing NRF2-mediated metabolic reprogramming in HPV-related HNSCC.
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Affiliation(s)
- Avani Vyas
- Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - R Alex Harbison
- Department of Otolaryngology, University of Washington School of Medicine, Seattle, Washington
| | - Daniel L Faden
- Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts
| | - Mark Kubik
- Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Drake Palmer
- Department of Biological Sciences, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Qing Zhang
- Genomics & Bioinformatics Shared Resources, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Hatice U Osmanbeyoglu
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.,Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Kirill Kiselyov
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Umamaheswar Duvvuri
- Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. .,UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.,VA Pittsburgh Healthcare System, U.S. Department of Veterans Affairs, Pittsburgh, Pennsylvania
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Yang CS, Chen XL. Research on esophageal cancer: With personal perspectives from studies in China and Kenya. Int J Cancer 2021; 149:264-276. [PMID: 33270917 PMCID: PMC8141013 DOI: 10.1002/ijc.33421] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 12/11/2022]
Abstract
The most common form of esophageal cancer (EC), esophageal squamous cell carcinoma (ESCC), is prevalent in many unindustrialized societies, among people with lower socioeconomic status and those who frequently use tobacco and alcohol. In some areas, ESCC mortality ranked top among all cancer. In this review, we begin with discussions of the extensive research on EC in Linxian in northern China that started 60 years ago and the recent studies in Kenya from our personal perspectives. Based on the results obtained from these studies and information from the literature, we summarize our current understanding about the risk factors for ESCC including lifestyle factors (smoking, alcohol, consumption of food and beverages at high temperature and other unhealthy habits), poor diet and nutritional insufficiencies and genetic susceptibility. Elimination or minimization of these environmental risk factors, as well as early detection and treatment of precancerous lesions, would be effective means for the prevention of ESCC. Current knowledge of molecular alterations in ESCC (gene mutations, hypermethylation and amplification or overexpression), as well as treatment of ESCC and the potential of targeted therapy, are also discussed. Finally, we propose effective approaches for the prevention of ESCC by adapting a healthy lifestyle, including a healthy diet that would also prevent other diseases. Community outreach, public education and international collaboration are important for achieving this public health goal.
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Affiliation(s)
- Chung S. Yang
- Department of Chemical BiologyErnest Mario School of Pharmacy, Rutgers, The State University of New JerseyPiscatawayNew JerseyUSA
| | - Xiaoxin Luke Chen
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central UniversityDurhamNorth CarolinaUSA
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Yin G, Huang J, Guo W, Huang Z. Metabolomics of Oral/Head and Neck Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1280:277-290. [PMID: 33791989 DOI: 10.1007/978-3-030-51652-9_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/21/2023]
Abstract
Oral/head and neck cancer is the sixth most common human malignancies in the world. Despite the treatment advances in surgery, chemotherapy, and radiotherapy, the patient survival has not been significantly improved in the past several decades. As a new methodological approach, metabolomics may help reveal the metabolic reprogramming mechanisms underlying head and neck cancer cell proliferation, invasion, and metastasis and may be used to identify metabolite biomarkers for clinical applications of the disease. In this chapter, we briefly review recent metabolomic applications in head and neck cancer.
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Affiliation(s)
- Gaofei Yin
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, China
| | - Junwei Huang
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, China
| | - Wei Guo
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, China
| | - Zhigang Huang
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Key Laboratory of Otolaryngology Head and Neck Surgery, Ministry of Education, Capital Medical University, Beijing, China.
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45
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Tang YC, Hsiao JR, Jiang SS, Chang JY, Chu PY, Liu KJ, Fang HL, Lin LM, Chen HH, Huang YW, Chen YT, Tsai FY, Lin SF, Chuang YJ, Kuo CC. c-MYC-directed NRF2 drives malignant progression of head and neck cancer via glucose-6-phosphate dehydrogenase and transketolase activation. Theranostics 2021; 11:5232-5247. [PMID: 33859744 PMCID: PMC8039948 DOI: 10.7150/thno.53417] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 02/17/2021] [Indexed: 02/06/2023] Open
Abstract
Rationale: NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact and regulatory mechanisms remain unclear. Methods: The protein expression of NRF2 in HNSCC specimens was examined by IHC. The regulatory effect of c-MYC on NRF2 was validated by ChIP-qPCR, RT-qPCR and western blot. The impacts of NRF2 on malignant progression of HNSCC were determined through genetic manipulation and pharmacological inhibition in vitro and in vivo. The gene-set enrichment analysis (GSEA) on expression data of cDNA microarray combined with ChIP-qPCR, RT-qPCR, western blot, transwell migration/ invasion, cell proliferation and soft agar colony formation assays were used to investigate the regulatory mechanisms of NRF2. Results: NRF2 expression is positively correlated with malignant features of HNSCC. In addition, carcinogens, such as nicotine and arecoline, trigger c-MYC-directed NRF2 activation in HNSCC cells. NRF2 reprograms a wide range of cancer metabolic pathways and the most notable is the pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) are critical downstream effectors of NRF2 that drive malignant progression of HNSCC; the coherently expressed signature NRF2/G6PD/TKT gene set is a potential prognostic biomarker for prediction of patient overall survival. Notably, G6PD- and TKT-regulated nucleotide biosynthesis is more important than redox regulation in determining malignant progression of HNSCC. Conclusions: Carcinogens trigger c-MYC-directed NRF2 activation. Over-activation of NRF2 promotes malignant progression of HNSCC through reprogramming G6PD- and TKT-mediated nucleotide biosynthesis. Targeting NRF2-directed cellular metabolism is an effective strategy for development of novel treatments for head and neck cancer.
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46
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Choe JH, Mazambani S, Kim TH, Kim JW. Oxidative Stress and the Intersection of Oncogenic Signaling and Metabolism in Squamous Cell Carcinomas. Cells 2021; 10:606. [PMID: 33803326 PMCID: PMC8000417 DOI: 10.3390/cells10030606] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/25/2021] [Accepted: 03/03/2021] [Indexed: 12/13/2022] Open
Abstract
Squamous cell carcinomas (SCCs) arise from both stratified squamous and non-squamous epithelium of diverse anatomical sites and collectively represent one of the most frequent solid tumors, accounting for more than one million cancer deaths annually. Despite this prevalence, SCC patients have not fully benefited from recent advances in molecularly targeted therapy or immunotherapy. Rather, decades old platinum-based or radiation regimens retaining limited specificity to the unique characteristics of SCC remain first-line treatment options. Historically, a lack of a consolidated perspective on genetic aberrations driving oncogenic transformation and other such factors essential for SCC pathogenesis and intrinsic confounding cellular heterogeneity in SCC have contributed to a critical dearth in effective and specific therapies. However, emerging evidence characterizing the distinct genomic, epigenetic, and metabolic landscapes of SCC may be elucidating unifying features in a seemingly heterogeneous disease. In this review, by describing distinct metabolic alterations and genetic drivers of SCC revealed by recent studies, we aim to establish a conceptual framework for a previously unappreciated network of oncogenic signaling, redox perturbation, and metabolic reprogramming that may reveal targetable vulnerabilities at their intersection.
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Affiliation(s)
- Joshua H. Choe
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Simbarashe Mazambani
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA; (S.M.); (T.H.K.)
| | - Tae Hoon Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA; (S.M.); (T.H.K.)
| | - Jung-whan Kim
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA; (S.M.); (T.H.K.)
- Research and Development, VeraVerse Inc., 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea
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Hiebert P. The Nrf2 transcription factor: A multifaceted regulator of the extracellular matrix. Matrix Biol Plus 2021; 10:100057. [PMID: 34195594 PMCID: PMC8233472 DOI: 10.1016/j.mbplus.2021.100057] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/13/2021] [Accepted: 01/13/2021] [Indexed: 02/06/2023] Open
Abstract
The transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) is widely recognized as a master regulator of the cellular stress response by facilitating the transcription of cytoprotective genes. As such, the Nrf2 pathway is critical in guarding the cell from the harmful effects of excessive reactive oxygen species/reactive nitrogen species (ROS/RNS) and in maintaining cellular redox balance. While excessive ROS/RNS are harmful to the cell, physiological levels of ROS/RNS play important roles in regulating numerous signaling pathways important for normal cellular function, including the synthesis of extracellular matrix (ECM). Recent advances have underscored the importance of ROS/RNS, and by extension, factors that influence redox-balance such as Nrf2, in regulating ECM production and deposition. In addition to reducing the oxidative burden in the cell, the discovery that Nrf2 can also directly target genes that regulate and form the ECM has cemented it as a multifaceted player in the regulation of ECM proteins, and provides new insight into its potential usefulness as a target for treating ECM-related pathologies.
Reactive oxygen/nitrogen species regulate extracellular matrix. Nrf2 can directly target extracellular matrix gene transcription. Regulation of extracellular matrix by Nrf2 potentially impacts tissue repair/cancer.
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Affiliation(s)
- Paul Hiebert
- Institute for Molecular Health Sciences, Department of Biology, ETH Zürich, Zürich 8093, Switzerland
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48
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NRF2/ACSS2 axis mediates the metabolic effect of alcohol drinking on esophageal squamous cell carcinoma. Biochem J 2021; 477:3075-3089. [PMID: 32776152 DOI: 10.1042/bcj20200452] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 08/01/2020] [Accepted: 08/07/2020] [Indexed: 12/24/2022]
Abstract
Alcohol drinking is a leading risk factor for the development of esophageal squamous cell carcinoma (ESCC). However, the molecular mechanisms of alcohol-associated ESCC remain poorly understood. One of the most commonly mutated genes in ESCC is nuclear factor erythroid 2 like 2 (NFE2L2 or NRF2), which is a critical transcription factor regulating oxidative stress response and drug detoxification. When NRF2 is hyperactive in cancer cells, however, it leads to metabolic reprogramming, cell proliferation, chemoradioresistance, and poor prognosis. In this study, hyperactive NRF2 was found to up-regulate acetyl-CoA synthetase short-chain family members 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in ESCC cells and mouse esophagus. We also showed that knockdown of NRF2 or ACSS2 led to decreased ACSS2 expression, which in turn reduced the levels of acetyl-CoA and ATP with or without ethanol exposure. In addition, ethanol exposure enhanced lipid synthesis in ESCC cells. Moreover, we observed a change in the metabolic profile of ESCC cells exposed to ethanol as a result of their NRF2 or ACSS2 status. We further showed that ACSS2 contributed to the invasive capability of NRF2high ESCC cells exposed to ethanol. In conclusion, the NRF2/ACSS2 axis mediates the metabolic effect of alcohol drinking on ESCC.
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49
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Baumel-Alterzon S, Katz LS, Brill G, Garcia-Ocaña A, Scott DK. Nrf2: The Master and Captain of Beta Cell Fate. Trends Endocrinol Metab 2021; 32:7-19. [PMID: 33243626 PMCID: PMC7746592 DOI: 10.1016/j.tem.2020.11.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/30/2020] [Accepted: 11/01/2020] [Indexed: 02/07/2023]
Abstract
Prolonged hyperglycemia is toxic to pancreatic β cells, generating excessive reactive oxygen species, defective glucose-stimulated insulin secretion, decreased insulin production, and eventually β cell death and diabetes. Nrf2 is a master regulator of cellular responses to counteract dangerous levels of oxidative stress. Maintenance of β cell mass depends on Nrf2 to promote the survival, function, and proliferation of β cells. Indeed, Nrf2 activation decreases inflammation, increases insulin sensitivity, reduces body weight, and preserves β cell mass. Therefore, numerous pharmacological activators of Nrf2 are being tested in clinical trials for the treatment of diabetes and diabetic complications. Modulating Nrf2 activity in β cells is a promising therapeutic approach for the treatment of diabetes.
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Affiliation(s)
- Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Liora S Katz
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Gabriel Brill
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adolfo Garcia-Ocaña
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Donald K Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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50
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Liao G, Liang X, Ping Y, Zhang Y, Liao J, Wang Y, Hou X, Jiang Z, Dong X, Xu C, Xiao Y. Revealing the subtyping of non-small cell lung cancer based on genomic evolutionary patterns by multi-region sequencing. Cancer Med 2020; 9:9485-9498. [PMID: 33078899 PMCID: PMC7774747 DOI: 10.1002/cam4.3541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 09/12/2020] [Accepted: 09/28/2020] [Indexed: 12/16/2022] Open
Abstract
Accurately classifying patients with non-small cell lung cancer (NSCLC) from the perspective of tumor evolution has not been systematically studied to date. Here, we reconstructed phylogenetic relationships of somatic mutations in 100 early NSCLC patients (327 lesions) through reanalyzing the TRACERx data. Based on the genomic evolutionary patterns presented on the phylogenetic trees, we grouped NSCLC patients into three evolutionary subtypes. The phylogenetic trees among three subtypes exhibited distinct branching structures, with one subtype representing branched evolution and another reflecting the early accumulation of genomic variation. However, in the evolutionary pattern of the third subtype, some mutations experienced selective sweeps and were gradually replaced by multiple newly formed subclonal populations. The subtype patients with poor prognosis had higher intra-tumor heterogeneity and subclonal diversity. We combined genomic heterogeneity with clinical phenotypes analysis and found that subclonal expansion results in the progression and deterioration of the tumor. The molecular mechanisms of subtype-specific Early Driver Feature (EDF) genes differed across the evolutionary subtypes, reflecting the characteristics of the subtype itself. In summary, our study provided new insights on the stratification of NSCLC patients based on genomic evolution that can be valuable for us to understand the development of pulmonary tumor profoundly.
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Affiliation(s)
- Gaoming Liao
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Xin Liang
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Yanyan Ping
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Yong Zhang
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Jianlong Liao
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Yihan Wang
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Xiaobo Hou
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Zedong Jiang
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Xiaoqiu Dong
- The Fourth Hospital of Harbin Medical UniversityHarbinChina
| | - Chaohan Xu
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Yun Xiao
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
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