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Wang TT, Han T, Xiao X, Guo D, Sun X, Liu Y, Zhao L, Xu H, Li R, Jiang L, Zhang B, Chen B, Wang S, Wang H, Wang X, Zhang M, Zhang S, Wang J, Qu J, Chen HZ, Liu DP, Zhang X, Wang M. SIRT3 deficiency reduces PFKFB3-driven T-cell glycolysis and promotes arthritic inflammation. SCIENCE CHINA. LIFE SCIENCES 2025:10.1007/s11427-024-2823-2. [PMID: 40029452 DOI: 10.1007/s11427-024-2823-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 12/18/2024] [Indexed: 03/05/2025]
Abstract
Cell metabolism is an indispensable biochemical process that provides the basic energy and materials necessary for normal cell function. Accumulating evidence implicates abnormal metabolism of T cells as playing a critical role in the pathogenesis of rheumatoid arthritis (RA). The deacetylase SIRT3 has been shown to directly regulate energy metabolism in nonimmune cells. However, the role of SIRT3 in T cells and whether it participates in RA process remain unclear. In this study, we demonstrated that T-cell glycolysis was inhibited after SIRT3 deficiency. Compared to wild-type mice, SIRT3 knockout mice exhibited more severe arthritis, cartilage erosion, and inflammation after immunization with antigen-induced arthritis (AIA). It is interesting to note that SIRT3 deficiency reduced the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting enzyme in glycolysis. Overexpression of PFKFB3 was shown to restore the impaired ATP production caused by SIRT3 deficiency in T cells, and protects T cells from apoptosis. In summary, SIRT3 plays an important role in the regulation of T-cell metabolism in the pathogenesis of RA. SIRT3 deficiency decreases glycolysis, reduces ATP production, induces apoptosis in CD4+ T cells, and further promotes AIA in mice.
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Affiliation(s)
- Ting-Ting Wang
- Clinical Biobank, Institute of Clinical Medicine, National Infrastructures for Translational Medicine, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Taotao Han
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Biomedical Engineering Facility of National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Key Laboratory of Gut Microbiota Translational Medicine Research, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Xinyue Xiao
- Department of Rheumatology, Key Laboratory of Myositis, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Dan Guo
- Clinical Biobank, Institute of Clinical Medicine, National Infrastructures for Translational Medicine, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xin Sun
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - Yudong Liu
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Lidan Zhao
- Department of Rheumatology & Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Haojie Xu
- Department of Rheumatology & Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Rong Li
- Department of Rheumatology & Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Lingjuan Jiang
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Bo Zhang
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Beidi Chen
- Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, 100191, China
| | - Shengru Wang
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Han Wang
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xiaoxi Wang
- Clinical Biobank, Institute of Clinical Medicine, National Infrastructures for Translational Medicine, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Miao Zhang
- Clinical Biobank, Institute of Clinical Medicine, National Infrastructures for Translational Medicine, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Sumei Zhang
- Clinical Biobank, Institute of Clinical Medicine, National Infrastructures for Translational Medicine, State Key Laboratory of Complex, Severe, and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Jian Wang
- Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Jiahua Qu
- Department of Host-Microbe Interactions, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA
| | - Hou-Zao Chen
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China
| | - De-Pei Liu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Min Wang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Wang C, Ma X. The role of acetylation and deacetylation in cancer metabolism. Clin Transl Med 2025; 15:e70145. [PMID: 39778006 PMCID: PMC11706801 DOI: 10.1002/ctm2.70145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/02/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
As a hallmark of cancer, metabolic reprogramming adjusts macromolecular synthesis, energy metabolism and redox homeostasis processes to adapt to and promote the complex biological processes of abnormal growth and proliferation. The complexity of metabolic reprogramming lies in its precise regulation by multiple levels and factors, including the interplay of multiple signalling pathways, precise regulation of transcription factors and dynamic adjustments in metabolic enzyme activity. In this complex regulatory network, acetylation and deacetylation, which are important post-translational modifications, regulate key molecules and processes related to metabolic reprogramming by affecting protein function and stability. Dysregulation of acetylation and deacetylation may alter cancer cell metabolic patterns by affecting signalling pathways, transcription factors and metabolic enzyme activity related to metabolic reprogramming, increasing the susceptibility to rapid proliferation and survival. In this review, we focus on discussing how acetylation and deacetylation regulate cancer metabolism, thereby highlighting the central role of these post-translational modifications in metabolic reprogramming, and hoping to provide strong support for the development of novel cancer treatment strategies. KEY POINTS: Protein acetylation and deacetylation are key regulators of metabolic reprogramming in tumour cells. These modifications influence signalling pathways critical for tumour metabolism. They modulate the activity of transcription factors that drive gene expression changes. Metabolic enzymes are also affected, altering cellular metabolism to support tumour growth.
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Affiliation(s)
- Cuicui Wang
- Department of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyang CityLiaoning ProvinceChina
- Key Laboratory of Gynecological Oncology of Liaoning ProvinceDepartment of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina
| | - Xiaoxin Ma
- Department of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyang CityLiaoning ProvinceChina
- Key Laboratory of Gynecological Oncology of Liaoning ProvinceDepartment of Obstetrics and GynecologyShengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina
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Kamal S, Babar S, Ali W, Rehman K, Hussain A, Akash MSH. Sirtuin insights: bridging the gap between cellular processes and therapeutic applications. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:9315-9344. [PMID: 38976046 DOI: 10.1007/s00210-024-03263-9] [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: 03/19/2024] [Accepted: 06/24/2024] [Indexed: 07/09/2024]
Abstract
The greatest challenges that organisms face today are effective responses or detection of life-threatening environmental changes due to an obvious semblance of stress and metabolic fluctuations. These are associated with different pathological conditions among which cancer is most important. Sirtuins (SIRTs; NAD+-dependent enzymes) are versatile enzymes with diverse substrate preferences, cellular locations, crucial for cellular processes and pathological conditions. This article describes in detail the distinct roles of SIRT isoforms, unveiling their potential as either cancer promoters or suppressors and also explores how both natural and synthetic compounds influence the SIRT function, indicating promise for therapeutic applications. We also discussed the inhibitors/activators tailored to specific SIRTs, holding potential for diseases lacking effective treatments. It may uncover the lesser-studied SIRT isoforms (e.g., SIRT6, SIRT7) and their unique functions. This article also offers a comprehensive overview of SIRTs, linking them to a spectrum of diseases and highlighting their potential for targeted therapies, combination approaches, disease management, and personalized medicine. We aim to contribute to a transformative era in healthcare and innovative treatments by unraveling the intricate functions of SIRTs.
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Affiliation(s)
- Shagufta Kamal
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Sharon Babar
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Waqas Ali
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, The Women University, Multan, Pakistan
| | - Amjad Hussain
- Institute of Chemistry, University of Okara, Okara, Punjab, Pakistan
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Shen H, Qi X, Hu Y, Wang Y, Zhang J, Liu Z, Qin Z. Targeting sirtuins for cancer therapy: epigenetics modifications and beyond. Theranostics 2024; 14:6726-6767. [PMID: 39479446 PMCID: PMC11519805 DOI: 10.7150/thno.100667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 09/29/2024] [Indexed: 11/02/2024] Open
Abstract
Sirtuins (SIRTs) are well-known as nicotinic adenine dinucleotide+(NAD+)-dependent histone deacetylases, which are important epigenetic enzymes consisting of seven family members (SIRT1-7). Of note, SIRT1 and SIRT2 are distributed in the nucleus and cytoplasm, while SIRT3, SIRT4 and SIRT5 are localized in the mitochondria. SIRT6 and SIRT7 are distributed in the nucleus. SIRTs catalyze the deacetylation of various substrate proteins, thereby modulating numerous biological processes, including transcription, DNA repair and genome stability, metabolism, and signal transduction. Notably, accumulating evidence has recently underscored the multi-faceted roles of SIRTs in both the suppression and progression of various types of human cancers. Crucially, SIRTs have been emerging as promising therapeutic targets for cancer therapy. Thus, in this review, we not only present an overview of the molecular structure and function of SIRTs, but elucidate their intricate associations with oncogenesis. Additionally, we discuss the current landscape of small-molecule activators and inhibitors targeting SIRTs in the contexts of cancer and further elaborate their combination therapies, especially highlighting their prospective utility for future cancer drug development.
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Affiliation(s)
- Hui Shen
- Department of Respiratory and Critical Care Medicine, Department of Outpatient, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xinyi Qi
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Yue Hu
- Department of Respiratory and Critical Care Medicine, Department of Outpatient, The First Hospital of China Medical University, Shenyang 110001, China
| | - Yi Wang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- No. 989 Hospital of Joint Logistic Support Force of PLA, Luoyang 471031, China
| | - Jin Zhang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Zhongyu Liu
- No. 989 Hospital of Joint Logistic Support Force of PLA, Luoyang 471031, China
| | - Zheng Qin
- Department of Respiratory and Critical Care Medicine, Department of Outpatient, The First Hospital of China Medical University, Shenyang 110001, China
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Panda B, Tripathy A, Patra S, Kullu B, Tabrez S, Jena M. Imperative connotation of SODs in cancer: Emerging targets and multifactorial role of action. IUBMB Life 2024; 76:592-613. [PMID: 38600696 DOI: 10.1002/iub.2821] [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: 01/08/2024] [Accepted: 03/14/2024] [Indexed: 04/12/2024]
Abstract
Superoxide dismutase (SOD) is a crucial enzyme responsible for the redox homeostasis inside the cell. As a part of the antioxidant defense system, it plays a pivotal role in the dismutation of the superoxide radicals (O 2 - ) generated mainly by the oxidative phosphorylation, which would otherwise bring out the redox dysregulation, leading to higher reactive oxygen species (ROS) generation and, ultimately, cell transformation, and malignancy. Several studies have shown the involvement of ROS in a wide range of human cancers. As SOD is the key enzyme in regulating ROS, any change, such as a transcriptional change, epigenetic remodeling, functional alteration, and so forth, either activates the proto-oncogenes or aberrant signaling cascades, which results in cancer. Interestingly, in some cases, SODs act as tumor promoters instead of suppressors. Furthermore, SODs have also been known to switch their role during tumor progression. In this review, we have tried to give a comprehensive account of SODs multifactorial role in various human cancers so that SODs-based therapeutic strategies could be made to thwart cancers.
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Affiliation(s)
- Biswajit Panda
- Department of Zoology, College of Basic Science and Humanities, Odisha University of Agriculture and Technology, Bhubaneswar, India
| | - Ankita Tripathy
- Post Graduate Department of Botany, Utkal University, Bhubaneswar, India
| | - Srimanta Patra
- Post Graduate Department of Botany, Berhampur University, Berhampur, India
| | - Bandana Kullu
- Post Graduate Department of Botany, Utkal University, Bhubaneswar, India
| | - Shams Tabrez
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mrutyunjay Jena
- Post Graduate Department of Botany, Berhampur University, Berhampur, India
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Trinh D, Al Halabi L, Brar H, Kametani M, Nash JE. The role of SIRT3 in homeostasis and cellular health. Front Cell Neurosci 2024; 18:1434459. [PMID: 39157755 PMCID: PMC11327144 DOI: 10.3389/fncel.2024.1434459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 06/25/2024] [Indexed: 08/20/2024] Open
Abstract
Mitochondria are responsible for maintaining cellular energy levels, and play a major role in regulating homeostasis, which ensures physiological function from the molecular to whole animal. Sirtuin 3 (SIRT3) is the major protein deacetylase of mitochondria. SIRT3 serves as a nutrient sensor; under conditions of mild metabolic stress, SIRT3 activity is increased. Within the mitochondria, SIRT3 regulates every complex of the electron transport chain, the tricarboxylic acid (TCA) and urea cycles, as well as the mitochondria membrane potential, and other free radical scavengers. This article reviews the role of SIRT3 in regulating homeostasis, and thus physiological function. We discuss the role of SIRT3 in regulating reactive oxygen species (ROS), ATP, immunological function and mitochondria dynamics.
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Affiliation(s)
- Dennison Trinh
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Lina Al Halabi
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Harsimar Brar
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Marie Kametani
- Department of Biological Sciences, University of Toronto, Toronto, ON, Canada
| | - Joanne E. Nash
- Department of Biological Sciences, University of Toronto Scarborough Graduate Department of Cells Systems Biology, University of Toronto Cross-Appointment with Department of Psychology, University of Toronto Scarborough Scientist – KITE, Toronto, ON, Canada
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Aventaggiato M, Arcangeli T, Vernucci E, Barreca F, Sansone L, Pellegrini L, Pontemezzo E, Valente S, Fioravanti R, Russo MA, Mai A, Tafani M. Pharmacological Activation of SIRT3 Modulates the Response of Cancer Cells to Acidic pH. Pharmaceuticals (Basel) 2024; 17:810. [PMID: 38931477 DOI: 10.3390/ph17060810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/14/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
Cancer cells modulate their metabolism, creating an acidic microenvironment that, in turn, can favor tumor progression and chemotherapy resistance. Tumor cells adopt strategies to survive a drop in extracellular pH (pHe). In the present manuscript, we investigated the contribution of mitochondrial sirtuin 3 (SIRT3) to the adaptation and survival of cancer cells to a low pHe. SIRT3-overexpressing and silenced breast cancer cells MDA-MB-231 and human embryonic kidney HEK293 cells were grown in buffered and unbuffered media at pH 7.4 and 6.8 for different times. mRNA expression of SIRT3 and CAVB, was measured by RT-PCR. Protein expression of SIRT3, CAVB and autophagy proteins was estimated by western blot. SIRT3-CAVB interaction was determined by immunoprecipitation and proximity ligation assays (PLA). Induction of autophagy was studied by western blot and TEM. SIRT3 overexpression increases the survival of both cell lines. Moreover, we demonstrated that SIRT3 controls intracellular pH (pHi) through the regulation of mitochondrial carbonic anhydrase VB (CAVB). Interestingly, we obtained similar results by using MC2791, a new SIRT3 activator. Our results point to the possibility of modulating SIRT3 to decrease the response and resistance of tumor cells to the acidic microenvironment and ameliorate the effectiveness of anticancer therapy.
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Affiliation(s)
- Michele Aventaggiato
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Tania Arcangeli
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Enza Vernucci
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Federica Barreca
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Luigi Sansone
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy
- Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Rome, Via di Val Cannuta 247, 00166 Rome, Italy
| | - Laura Pellegrini
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Elena Pontemezzo
- European Hospital, New Fertility Group, Center for Reproductive Medicine, Via Portuense 700, 00149 Rome, Italy
| | - Sergio Valente
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Rossella Fioravanti
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Matteo Antonio Russo
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy
- Laboratory of Cellular and Molecular Pathology, IRCCS San Raffaele Rome, Via di Val Cannuta 247, 00166 Rome, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Marco Tafani
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
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Lambona C, Zwergel C, Valente S, Mai A. SIRT3 Activation a Promise in Drug Development? New Insights into SIRT3 Biology and Its Implications on the Drug Discovery Process. J Med Chem 2024; 67:1662-1689. [PMID: 38261767 PMCID: PMC10859967 DOI: 10.1021/acs.jmedchem.3c01979] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/14/2023] [Accepted: 12/20/2023] [Indexed: 01/25/2024]
Abstract
Sirtuins catalyze deacetylation of lysine residues with a NAD+-dependent mechanism. In mammals, the sirtuin family is composed of seven members, divided into four subclasses that differ in substrate specificity, subcellular localization, regulation, as well as interactions with other proteins, both within and outside the epigenetic field. Recently, much interest has been growing in SIRT3, which is mainly involved in regulating mitochondrial metabolism. Moreover, SIRT3 seems to be protective in diseases such as age-related, neurodegenerative, liver, kidney, heart, and metabolic ones, as well as in cancer. In most cases, activating SIRT3 could be a promising strategy to tackle these health problems. Here, we summarize the main biological functions, substrates, and interactors of SIRT3, as well as several molecules reported in the literature that are able to modulate SIRT3 activity. Among the activators, some derive from natural products, others from library screening, and others from the classical medicinal chemistry approach.
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Affiliation(s)
- Chiara Lambona
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Clemens Zwergel
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Sergio Valente
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
| | - Antonello Mai
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
- Pasteur
Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
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Qannita RA, Alalami AI, Harb AA, Aleidi SM, Taneera J, Abu-Gharbieh E, El-Huneidi W, Saleh MA, Alzoubi KH, Semreen MH, Hudaib M, Bustanji Y. Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation. Pharmaceuticals (Basel) 2024; 17:195. [PMID: 38399410 PMCID: PMC10892333 DOI: 10.3390/ph17020195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
Hypoxia-inducible factor-1 (HIF-1) is a key regulator for balancing oxygen in the cells. It is a transcription factor that regulates the expression of target genes involved in oxygen homeostasis in response to hypoxia. Recently, research has demonstrated the multiple roles of HIF-1 in the pathophysiology of various diseases, including cancer. It is a crucial mediator of the hypoxic response and regulator of oxygen metabolism, thus contributing to tumor development and progression. Studies showed that the expression of the HIF-1α subunit is significantly upregulated in cancer cells and promotes tumor survival by multiple mechanisms. In addition, HIF-1 has potential contributing roles in cancer progression, including cell division, survival, proliferation, angiogenesis, and metastasis. Moreover, HIF-1 has a role in regulating cellular metabolic pathways, particularly the anaerobic metabolism of glucose. Given its significant and potential roles in cancer development and progression, it has been an intriguing therapeutic target for cancer research. Several compounds targeting HIF-1-associated processes are now being used to treat different types of cancer. This review outlines emerging therapeutic strategies that target HIF-1 as well as the relevance and regulation of the HIF-1 pathways in cancer. Moreover, it addresses the employment of nanotechnology in developing these promising strategies.
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Affiliation(s)
- Reem A. Qannita
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (R.A.Q.); (A.I.A.); (J.T.); (E.A.-G.); (W.E.-H.); (M.A.S.); (K.H.A.); (M.H.S.)
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Ayah I. Alalami
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (R.A.Q.); (A.I.A.); (J.T.); (E.A.-G.); (W.E.-H.); (M.A.S.); (K.H.A.); (M.H.S.)
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Amani A. Harb
- Department of Basic Sciences, Faculty of Arts and Sciences, Al-Ahliyya Amman University, Amman 19111, Jordan;
| | - Shereen M. Aleidi
- School of Pharmacy, The University of Jordan, Amman 11942, Jordan; (S.M.A.); (M.H.)
| | - Jalal Taneera
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (R.A.Q.); (A.I.A.); (J.T.); (E.A.-G.); (W.E.-H.); (M.A.S.); (K.H.A.); (M.H.S.)
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Eman Abu-Gharbieh
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (R.A.Q.); (A.I.A.); (J.T.); (E.A.-G.); (W.E.-H.); (M.A.S.); (K.H.A.); (M.H.S.)
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- School of Pharmacy, The University of Jordan, Amman 11942, Jordan; (S.M.A.); (M.H.)
| | - Waseem El-Huneidi
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (R.A.Q.); (A.I.A.); (J.T.); (E.A.-G.); (W.E.-H.); (M.A.S.); (K.H.A.); (M.H.S.)
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Mohamed A. Saleh
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (R.A.Q.); (A.I.A.); (J.T.); (E.A.-G.); (W.E.-H.); (M.A.S.); (K.H.A.); (M.H.S.)
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Karem H. Alzoubi
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (R.A.Q.); (A.I.A.); (J.T.); (E.A.-G.); (W.E.-H.); (M.A.S.); (K.H.A.); (M.H.S.)
- Department of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Mohammad H. Semreen
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (R.A.Q.); (A.I.A.); (J.T.); (E.A.-G.); (W.E.-H.); (M.A.S.); (K.H.A.); (M.H.S.)
- Department of Medicinal Chemistry, College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Mohammad Hudaib
- School of Pharmacy, The University of Jordan, Amman 11942, Jordan; (S.M.A.); (M.H.)
| | - Yasser Bustanji
- Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; (R.A.Q.); (A.I.A.); (J.T.); (E.A.-G.); (W.E.-H.); (M.A.S.); (K.H.A.); (M.H.S.)
- College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- School of Pharmacy, The University of Jordan, Amman 11942, Jordan; (S.M.A.); (M.H.)
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10
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Habra K, Pearson JRD, Le Vu P, Puig‐Saenz C, Cripps MJ, Khan MA, Turner MD, Sale C, McArdle SEB. Anticancer actions of carnosine in cellular models of prostate cancer. J Cell Mol Med 2024; 28:e18061. [PMID: 38018900 PMCID: PMC10826443 DOI: 10.1111/jcmm.18061] [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: 04/19/2023] [Revised: 11/03/2023] [Accepted: 11/17/2023] [Indexed: 11/30/2023] Open
Abstract
Treatments for organ-confined prostate cancer include external beam radiation therapy, radical prostatectomy, radiotherapy/brachytherapy, cryoablation and high-intensity focused ultrasound. None of these are cancer-specific and are commonly accompanied by side effects, including urinary incontinence and erectile dysfunction. Moreover, subsequent surgical treatments following biochemical recurrence after these interventions are either limited or affected by the scarring present in the surrounding tissue. Carnosine (β-alanyl-L-histidine) is a histidine-containing naturally occurring dipeptide which has been shown to have an anti-tumorigenic role without any detrimental effect on healthy cells; however, its effect on prostate cancer cells has never been investigated. In this study, we investigated the effect of carnosine on cell proliferation and metabolism in both a primary cultured androgen-resistant human prostate cancer cell line, PC346Flu1 and murine TRAMP-C1 cells. Our results show that carnosine has a significant dose-dependent inhibitory effect in vitro on the proliferation of both human (PC346Flu1) and murine (TRAMP-C1) prostate cancer cells, which was confirmed in 3D-models of the same cells. Carnosine was also shown to decrease adenosine triphosphate content and reactive species which might have been caused in part by the increase in SIRT3 also shown after carnosine treatment. These encouraging results support the need for further human in vivo work to determine the potential use of carnosine, either alone or, most likely, as an adjunct therapy to surgical or other conventional treatments.
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Affiliation(s)
- K. Habra
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent UniversityNottinghamUK
- Chemistry Department, School of Science and TechnologyNottingham Trent UniversityNottinghamUK
| | - J. R. D. Pearson
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent UniversityNottinghamUK
- Centre for Systems Health and integrated Metabolic Research (SHiMR), School of Science and TechnologyNottingham Trent UniversityNottinghamUK
| | - P. Le Vu
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent UniversityNottinghamUK
| | - C. Puig‐Saenz
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent UniversityNottinghamUK
- Centre for Systems Health and integrated Metabolic Research (SHiMR), School of Science and TechnologyNottingham Trent UniversityNottinghamUK
| | - M. J. Cripps
- Centre for Diabetes, Chronic Diseases, and Ageing, School of Science and TechnologyNottingham Trent UniversityNottinghamUK
| | - M. A. Khan
- Department of UrologyUniversity Hospitals of Leicester NHS TrustLeicesterUK
| | - M. D. Turner
- Centre for Systems Health and integrated Metabolic Research (SHiMR), School of Science and TechnologyNottingham Trent UniversityNottinghamUK
- Centre for Diabetes, Chronic Diseases, and Ageing, School of Science and TechnologyNottingham Trent UniversityNottinghamUK
| | - C. Sale
- Institute of Sport, Manchester Metropolitan UniversityManchesterUK
| | - S. E. B. McArdle
- John van Geest Cancer Research Centre, School of Science and TechnologyNottingham Trent UniversityNottinghamUK
- Centre for Systems Health and integrated Metabolic Research (SHiMR), School of Science and TechnologyNottingham Trent UniversityNottinghamUK
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11
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Zhao X, Sun Y, Xu Z, Cai L, Hu Y, Wang H. Targeting PRMT1 prevents acute and chronic graft-versus-host disease. Mol Ther 2023; 31:3259-3276. [PMID: 37735873 PMCID: PMC10638063 DOI: 10.1016/j.ymthe.2023.09.011] [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: 02/28/2023] [Revised: 06/15/2023] [Accepted: 09/14/2023] [Indexed: 09/23/2023] Open
Abstract
Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic stem cell transplantation. Recent studies have reported that protein arginine methyltransferase 1 (PRMT1) is essential for the differentiation and proliferation of T and B cells. Therefore, it is possible that PRMT1 may play a critical role in GVHD. In this study, we observed that PRMT1 expression was upregulated in CD4+ T and B cells from chronic GVHD (cGVHD) patients and mice. However, the prophylactic use of a PRMT1 inhibitor significantly prevented cGVHD in mice by reducing the percentage of T helper (Th)17 cells, germinal center B cells, and plasma cells. The PRMT1 inhibitor also controlled acute GVHD (aGVHD) in mice by decreasing the percentage of Th17 cells. Moreover, inhibiting PRMT1 also weakened Th17 cell differentiation, B cell proliferation, and antibody production in cells from cGVHD patients. Additionally, further studies revealed that PRMT1 regulated B cell proliferation and antibody secretion by methylating isocitrate dehydrogenase 2 (IDH2). We observed asymmetric di-methylation of IDH2 by PRMT1 at arginine 353 promoted IDH2 homodimerization, which enhanced IDH2 activity, further increasing B cell proliferation and antibody production. Collectively, this study provides a rationale for the application of PRMT1 inhibitors in the prevention of aGVHD and cGVHD.
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Affiliation(s)
- Xiaoyan Zhao
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yan Sun
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ziwei Xu
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Li Cai
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yu Hu
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Huafang Wang
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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12
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Huang H, Zhang W, Su J, Zhou B, Han Q. Spermidine Retarded the Senescence of Multipotent Mesenchymal Stromal Cells In Vitro and In Vivo through SIRT3-Mediated Antioxidation. Stem Cells Int 2023; 2023:9672658. [PMID: 37234959 PMCID: PMC10208764 DOI: 10.1155/2023/9672658] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 04/18/2023] [Accepted: 04/29/2023] [Indexed: 05/28/2023] Open
Abstract
Multipotent mesenchymal stromal cells (MSCs) expand in vitro and undergo replicative senescence, thereby restricting their clinical utilization. Thus, an effective strategy is required to impede MSC senescence. Since spermidine (SPD) supplementation can prolong the lifespan of yeast by inhibiting oxidative stress, spermidine is a potential option for delaying MSC senescence. In this study, to test our hypothesis, we first isolated primary human umbilical cord mesenchymal stem cells (hUCMSCs). Subsequently, the appropriate SPD dose was administered during continuous cell cultivation. Next, we evaluated the antisenescence effects by SA-β-gal staining, Ki67 expression, reactive oxygen species (ROS) levels, adipogenic or osteogenic ability, senescence-associated markers, and DNA damage markers. The results revealed that early SPD intervention significantly delays the replicative senescence of hUCMSCs and constrains premature H2O2-induced senescence. Additionally, by silencing SIRT3, the SPD-mediated antisenescence effects disappear, further demonstrating that SIRT3 is necessary for SPD to exert its antisenescence effects on hUCMSCs. Besides, the findings of this study also suggest that SPD in vivo protects MSCs against oxidative stress and delays cell senescence. Thus, MSCs maintain the ability to proliferate and differentiate efficiently in vitro and in vivo, which reflects the potential clinical utilization of MSCs in the future.
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Affiliation(s)
- Hua Huang
- Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
- The Center of Reproductive Medicine, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Wen Zhang
- Department of General Medicine, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Junjie Su
- Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Bisheng Zhou
- Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Qingjiang Han
- Department of Urology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
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13
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Lee JH, Kang HI, Kim S, Ahn YB, Kim H, Hong JK, Baik JY. NAD + supplementation improves mAb productivity in CHO cells via a glucose metabolic shift. Biotechnol J 2023; 18:e2200570. [PMID: 36717516 DOI: 10.1002/biot.202200570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/22/2022] [Accepted: 01/19/2023] [Indexed: 02/01/2023]
Abstract
Aerobic glycolysis and its by-product lactate accumulation are usually associated with adverse culture phenotypes such as poor cell viability and productivity. Due to the lack of knowledge on underlying mechanisms and accompanying biological processes, the regulation of aerobic glycolysis has been an ongoing challenge in culture process development for therapeutic protein productivity. Nicotinamide adenine dinucleotide (NAD+ ), a coenzyme and co-substrate in energy metabolism, promotes the conversion of inefficient glycolysis into an efficient oxidative phosphorylation (OXPHOS) pathway. However, the effect of NAD+ on Chinese hamster ovary (CHO) cells for biopharmaceutical production has not been reported yet. In this work, we aimed to elucidate the influence of NAD+ on cell culture performance by examining metabolic shifts and mAb productivity. The supplementation of NAD+ increased the intracellular concentration of NAD+ and promoted SIRT3 expression. Antibody titer and the specific productivity in the growth phase were improved by up to 1.82- and 1.88-fold, respectively, with marginal restrictions on cell growth. NAD+ significantly reduced the accumulation of reactive oxygen species (ROS) and the lactate yield from glucose, determined by lactate accumulation versus glucose consumption (YLAC/GLC ). In contrast, OXPHOS capacity and amino acid consumption rate increased substantially. Collectively, these results suggest that NAD+ contributes to improving therapeutic protein productivity in bioprocessing via inducing an energy metabolic shift.
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Affiliation(s)
- Ji Hwan Lee
- Department of Biological Sciences and Bioengineering, Inha University, Incheon, South Korea
| | - Hye-Im Kang
- Department of Biological Sciences and Bioengineering, Inha University, Incheon, South Korea
| | - Suheon Kim
- Department of Biological Sciences and Bioengineering, Inha University, Incheon, South Korea
| | - Yeong Bin Ahn
- Division of Biological Science and Technology, Yonsei University, Wonju, Gangwon-do, Republic of Korea
| | - Hagyeong Kim
- Department of Biological Sciences and Bioengineering, Inha University, Incheon, South Korea
| | - Jong Kwang Hong
- Division of Biological Science and Technology, Yonsei University, Wonju, Gangwon-do, Republic of Korea
| | - Jong Youn Baik
- Department of Biological Sciences and Bioengineering, Inha University, Incheon, South Korea
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14
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Haq MFU, Hussain MZ, Mahjabeen I, Akram Z, Saeed N, Shafique R, Abbasi SF, Kayani MA. Oncometabolic role of mitochondrial sirtuins in glioma patients. PLoS One 2023; 18:e0281840. [PMID: 36809279 PMCID: PMC9943017 DOI: 10.1371/journal.pone.0281840] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 01/31/2023] [Indexed: 02/23/2023] Open
Abstract
Mitochondrial sirtuins have diverse role specifically in aging, metabolism and cancer. In cancer, these sirtuins play dichotomous role as tumor suppressor and promoter. Previous studies have reported the involvement of sirtuins in different cancers. However, till now no study has been published with respect to mitochondrial sirtuins and glioma risks. Present study was purposed to figure out the expression level of mitochondrial sirtuins (SIRT3, SIRT4, SIRT5) and related genes (GDH, OGG1-2α, SOD1, SOD2, HIF1α and PARP1) in 153 glioma tissue samples and 200 brain tissue samples from epilepsy patients (taken as controls). To understand the role of selected situins in gliomagenesis, DNA damage was measured using the comet assay and oncometabolic role (oxidative stress level, ATP level and NAD level) was measured using the ELISA and quantitative PCR. Results analysis showed significant down-regulation of SIRT4 (p = 0.0337), SIRT5 (p<0.0001), GDH (p = 0.0305), OGG1-2α (p = 0.0001), SOD1 (p<0.0001) and SOD2 (p<0.0001) in glioma patients compared to controls. In case of SIRT3 (p = 0.0322), HIF1α (p = 0.0385) and PARP1 (p = 0.0203), significant up-regulation was observed. ROC curve analysis and cox regression analysis showed the good diagnostic and prognostic value of mitochondrial sirtuins in glioma patients. Oncometabolic rate assessment analysis showed significant increased ATP level (p<0.0001), NAD+ level [(NMNAT1 (p<0.0001), NMNAT3 (p<0.0001) and NAMPT (p<0.04)] and glutathione level (p<0.0001) in glioma patients compared to controls. Significant increased level of damage ((p<0.04) and decrease level of antioxidant enzymes include superoxide dismutase (SOD, p<0.0001), catalase (CAT, p<0.0001) and glutathione peroxidase (GPx, p<0.0001) was observed in patients compared to controls. Present study data suggest that variation in expression pattern of mitochondrial sirtuins and increased metabolic rate may have diagnostic and prognostic significance in glioma patients.
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Affiliation(s)
- Maria Fazal Ul Haq
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | | | - Ishrat Mahjabeen
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
- * E-mail:
| | - Zertashia Akram
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Nadia Saeed
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Rabia Shafique
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Sumaira Fida Abbasi
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Cancer Genetics and Epigenetics Research Group, Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan
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15
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Ying M, Hu X. Tracing the electron flow in redox metabolism: The appropriate distribution of electrons is essential to maintain redox balance in cancer cells. Semin Cancer Biol 2022; 87:32-47. [PMID: 36374644 DOI: 10.1016/j.semcancer.2022.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 10/08/2022] [Accepted: 10/14/2022] [Indexed: 11/09/2022]
Abstract
Cancer cells are characterized by sustained proliferation, which requires a huge demand of fuels to support energy production and biosynthesis. Energy is produced by the oxidation of the fuels during catabolism, and biosynthesis is achieved by the reduction of smaller units or precursors. Therefore, the oxidation-reduction (redox) reactions in cancer cells are more active compared to those in the normal counterparts. The higher activity of redox metabolism also induces a more severe oxidative stress, raising the question of how cancer cells maintain the redox balance. In this review, we overview the redox metabolism of cancer cells in an electron-tracing view. The electrons are derived from the nutrients in the tumor microenvironment and released during catabolism. Most of the electrons are transferred to NAD(P) system and then directed to four destinations: energy production, ROS generation, reductive biosynthesis and antioxidant system. The appropriate distribution of these electrons achieved by the function of redox regulation network is essential to maintain redox homeostasis in cancer cells. Interfering with the electron distribution and disrupting redox balance by targeting the redox regulation network may provide therapeutic implications for cancer treatment.
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Affiliation(s)
- Minfeng Ying
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China.
| | - Xun Hu
- Cancer Institute (Key Laboratory for Cancer Intervention and Prevention, China National Ministry of Education, Zhejiang Provincial Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, 310009 Hangzhou, Zhejiang, China.
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16
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He Q, Chen J, Xie Z, Chen Z. Wild-Type Isocitrate Dehydrogenase-Dependent Oxidative Decarboxylation and Reductive Carboxylation in Cancer and Their Clinical Significance. Cancers (Basel) 2022; 14:cancers14235779. [PMID: 36497259 PMCID: PMC9741289 DOI: 10.3390/cancers14235779] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
The human isocitrate dehydrogenase (IDH) gene encodes for the isoenzymes IDH1, 2, and 3, which catalyze the conversion of isocitrate and α-ketoglutarate (α-KG) and are required for normal mammalian metabolism. Isocitrate dehydrogenase 1 and 2 catalyze the reversible conversion of isocitrate to α-KG. Isocitrate dehydrogenase 3 is the key enzyme that mediates the production of α-KG from isocitrate in the tricarboxylic acid (TCA) cycle. In the TCA cycle, the decarboxylation reaction catalyzed by isocitrate dehydrogenase mediates the conversion of isocitrate to α-KG accompanied by dehydrogenation, a process commonly known as oxidative decarboxylation. The formation of 6-C isocitrate from α-KG and CO2 catalyzed by IDH is termed reductive carboxylation. This IDH-mediated reversible reaction is of great importance in tumor cells. We outline the role of the various isocitrate dehydrogenase isoforms in cancer, discuss the metabolic implications of interference with IDH, summarize therapeutic interventions targeting changes in IDH expression, and highlight areas for future research.
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17
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Lin C, Xu JQ, Zhong GC, Chen H, Xue HM, Yang M, Chen C. Integrating RNA-seq and scRNA-seq to explore the biological significance of NAD + metabolism-related genes in the initial diagnosis and relapse of childhood B-cell acute lymphoblastic leukemia. Front Immunol 2022; 13:1043111. [PMID: 36439178 PMCID: PMC9691973 DOI: 10.3389/fimmu.2022.1043111] [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: 09/13/2022] [Accepted: 10/27/2022] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND Nicotinamide Adenine Dinucleotide (NAD) depletion is reported to be a potential treatment for B-cell Acute Lymphoblastic Leukemia (B-ALL), but the mechanism of NAD metabolism-related genes (NMRGs) in B-ALL relapse remains unclear. METHODS Transcriptome data (GSE3912), and single-cell sequencing data (GSE130116) of B-ALL patients were downloaded from Gene Expression Omnibus (GEO) database. NMRGs were sourced from Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases. Further, the differentially expressed NMRGs (DE-NMRGs) were selected from the analysis between initial diagnosis and relapse B-ALL samples, which further performed functional enrichment analyses. The biomarkers were obtained through random forest (RF) algorithm and repeated cross validation. Additionally, cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm was used to evaluate the immune cell differences between the initial diagnosis and relapse samples, and the correlations between biomarkers and gene markers of differential immune cells were analyzed. Furthermore, single cell RNA sequencing was conducted in the GSE130116 dataset to find key cell clusters. In addition, according to biomarkers expressions, cell clusters were categorized into high and low biomarker expression groups, and Gene Set Enrichment Analysis (GSEA) analysis was performed on them. Finally, the cell clusters with the highest expression of biomarkers were selected to explore the roles of biomarkers in different cell clusters and identify transcription factors (TFs) influencing biological markers. RESULTS 23 DE-NMRGs were screened out, which were mainly enriched in nucleoside phosphate metabolic process, nucleotide metabolic process, and Nicotinate and nicotinamide metabolism. Moreover, 3 biomarkers (NADSYN1, SIRT3, and PARP6) were identified from the machine learning. CIBERSORT results demonstrated that four types of immune cells (B Cells naive, Monocyte, Neutrophils, and T cells CD4 memory Activated) were significantly different between the initial diagnosis and the relapse B-ALL samples, and there were strong correlations between biomarkers and differential immune cells such as positive correlation between NADSYN1 and B Cells naive. The single cell analyses showed that the biomarkers were highly expressed in common myeloid progenitors (CMP), granulocyte-macrophage progenitor (GMP), and megakaryocyte-erythroid progenitor (MEP) cell clusters. Gene set enrichment analysis (GSEA) results indicated that 55 GO terms and 3 KEGG pathways were enriched by the genes in high and low biomarker expression groups. It was found that TF CREB3L2(+) was significantly reduced in the high expression group, which may be the TF affecting biomarkers in the high expression group. CONCLUSION This study identified NADSYN1, SIRT3, and PARP6 as the biomarkers of B-ALL, explored biological significance of NMRGs in the initial diagnosis and relapse of B-ALL, and revealed mechanism of biomarkers at the level of the single cell.
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Affiliation(s)
- Chao Lin
- Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Jia-Qi Xu
- Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Gui-Chao Zhong
- Department of Pediatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China
| | - Hui Chen
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Hong-Man Xue
- Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Mo Yang
- Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Chun Chen
- Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
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18
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Markouli M, Strepkos D, Piperi C. Impact of Histone Modifications and Their Therapeutic Targeting in Hematological Malignancies. Int J Mol Sci 2022; 23:13657. [PMID: 36362442 PMCID: PMC9654260 DOI: 10.3390/ijms232113657] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/31/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
Hematologic malignancies are a large and heterogeneous group of neoplasms characterized by complex pathogenetic mechanisms. The abnormal regulation of epigenetic mechanisms and specifically, histone modifications, has been demonstrated to play a central role in hematological cancer pathogenesis and progression. A variety of epigenetic enzymes that affect the state of histones have been detected as deregulated, being either over- or underexpressed, which induces changes in chromatin compaction and, subsequently, affects gene expression. Recent advances in the field of epigenetics have revealed novel therapeutic targets, with many epigenetic drugs being investigated in clinical trials. The present review focuses on the biological impact of histone modifications in the pathogenesis of hematologic malignancies, describing a wide range of therapeutic agents that have been discovered to target these alterations and are currently under investigation in clinical trials.
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Affiliation(s)
| | | | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (M.M.); (D.S.)
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19
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Role of Sirtuins in the Pathobiology of Onco-Hematological Diseases: A PROSPERO-Registered Study and In Silico Analysis. Cancers (Basel) 2022; 14:cancers14194611. [PMID: 36230534 PMCID: PMC9561980 DOI: 10.3390/cancers14194611] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary The aging of the hematological system can cause physiological disorders such as anemia, reduced immunity, and the increased incidence of blood cancer. Patients diagnosed with hematologic malignancies comprise nearly 10% of all cancer deaths identified in international epidemiologic studies. Therefore, it is considered a public health problem worldwide. Scientific evidence demonstrates the important involvement of sirtuins (SIRTs) in the pathogenesis of several types of solid tumors. However, the role of SIRTs in the pathobiology of malignant hematological diseases has not yet been systematically reviewed. In this systematic review, we highlight the role of different SIRTs in the pathogenesis of acute and chronic leukemias, lymphoma and myeloma. Also, we performed a bioinformatic analysis to identify whether the expression of SIRTs is altered in onco-hematological diseases, such as lymphomas and leukemias. The advent of new applicability of SIRTs in the process of aging and hematological carcinogenesis may allow the development of new diagnostic and therapeutic approaches for these diseases. Abstract The sirtuins (SIRT) gene family (SIRT1 to SIRT7) contains the targets implicated in cellular and organismal aging. The role of SIRTs expression in the pathogenesis and overall survival of patients diagnosed with solid tumors has been widely discussed. However, studies that seek to explain the role of these pathways in the hematopoietic aging process and the consequences of their instability in the pathogenesis of different onco-hematological diseases are still scarce. Therefore, we performed a systematic review (registered in PROSPERO database #CRD42022310079) and in silico analysis (based on GEPIA database) to discuss the role of SIRTs in the advancement of pathogenesis and/or prognosis for different hematological cancer types. In summary, given recent available scientific evidence and in silico gene expression analysis that supports the role of SIRTs in pathobiology of hematological malignances, such as leukemias, lymphomas and myeloma, it is clear the need for further high-quality research and clinical trials that expands the SIRT inhibition knowledge and its effect on controlling clonal progression caused by genomic instability characteristics of these diseases. Finally, SIRTs represent potential molecular targets in the control of the effects caused by aging on the failures of the hematopoietic system that can lead to the involvement of hematological neoplasms.
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Otsuka R, Hayano K, Matsubara H. Role of sirtuins in esophageal cancer: Current status and future prospects. World J Gastrointest Oncol 2022; 14:794-807. [PMID: 35582109 PMCID: PMC9048530 DOI: 10.4251/wjgo.v14.i4.794] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/02/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer (EC) is a malignant cancer that still has a poor prognosis, although its prognosis has been improving with the development of multidisciplinary treatment modalities such as surgery, chemotherapy and radiotherapy. Therefore, identifying specific molecular markers that can be served as biomarkers for the prognosis and treatment response of EC is highly desirable to aid in the personalization and improvement of the precision of medical treatment. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+)-dependent proteins consisting of seven members (SIRT1-7). These proteins have been reported to be involved in the regulation of a variety of biological functions including apoptosis, metabolism, stress response, senescence, differentiation and cell cycle progression. Given the variety of functions of sirtuins, they are speculated to be associated in some manner with cancer progression. However, while the role of sirtuins in cancer progression has been investigated over the past few years, their precise role remains difficult to characterize, as they have both cancer-promoting and cancer-suppressing properties, depending on the type of cancer. These conflicting characteristics make research into the nature of sirtuins all the more fascinating. However, the role of sirtuins in EC remains unclear due to the limited number of reports concerning sirtuins in EC. We herein review the current findings and future prospects of sirtuins in EC.
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Affiliation(s)
- Ryota Otsuka
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Koichi Hayano
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
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21
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SOD2, a Potential Transcriptional Target Underpinning CD44-Promoted Breast Cancer Progression. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030811. [PMID: 35164076 PMCID: PMC8839817 DOI: 10.3390/molecules27030811] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 11/17/2022]
Abstract
CD44, a cell-adhesion molecule has a dual role in tumor growth and progression; it acts as a tumor suppressor as well as a tumor promoter. In our previous work, we developed a tetracycline-off regulated expression of CD44's gene in the breast cancer (BC) cell line MCF-7 (B5 clone). Using cDNA oligo gene expression microarray, we identified SOD2 (superoxide dismutase 2) as a potential CD44-downstream transcriptional target involved in BC metastasis. SOD2 gene belongs to the family of iron/manganese superoxide dismutase family and encodes a mitochondrial protein. SOD2 plays a role in cell proliferation and cell invasion via activation of different signaling pathways regulating angiogenic abilities of breast tumor cells. This review will focus on the findings supporting the underlying mechanisms associated with the oncogenic potential of SOD2 in the onset and progression of cancer, especially in BC and the potential clinical relevance of its various inhibitors.
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Fernández-Serrano M, Winkler R, Santos JC, Le Pannérer MM, Buschbeck M, Roué G. Histone Modifications and Their Targeting in Lymphoid Malignancies. Int J Mol Sci 2021; 23:253. [PMID: 35008680 PMCID: PMC8745418 DOI: 10.3390/ijms23010253] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Abstract
In a wide range of lymphoid neoplasms, the process of malignant transformation is associated with somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction, and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes. In the last two decades, the field has made a major effort to develop therapies that target these epigenetic alterations. In this review, we discuss which epigenetic alterations occur in B-cell non-Hodgkin lymphoma. Furthermore, we aim to present in a close to comprehensive manner the current state-of-the-art in the preclinical and clinical development of epigenetic drugs. We focus on therapeutic strategies interfering with histone methylation and acetylation as these are most advanced in being deployed from the bench-to-bedside and have the greatest potential to improve the prognosis of lymphoma patients.
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Affiliation(s)
- Miranda Fernández-Serrano
- Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (M.F.-S.); (J.C.S.)
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08014 Barcelona, Spain
| | - René Winkler
- Chromatin, Metabolism and Cell Fate Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (R.W.); (M.-M.L.P.)
| | - Juliana C. Santos
- Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (M.F.-S.); (J.C.S.)
| | - Marguerite-Marie Le Pannérer
- Chromatin, Metabolism and Cell Fate Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (R.W.); (M.-M.L.P.)
| | - Marcus Buschbeck
- Chromatin, Metabolism and Cell Fate Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (R.W.); (M.-M.L.P.)
- Program of Personalized and Predictive Medicine of Cancer, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain
| | - Gaël Roué
- Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, Spain; (M.F.-S.); (J.C.S.)
- Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, 08014 Barcelona, Spain
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Sirtuins as Metabolic Regulators of Immune Cells Phenotype and Function. Genes (Basel) 2021; 12:genes12111698. [PMID: 34828304 PMCID: PMC8618532 DOI: 10.3390/genes12111698] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 12/28/2022] Open
Abstract
Beyond its role on the conversion of nutrients into energy and biomass, cellular metabolism is actively involved in the control of many physiological processes. Among these, it is becoming increasingly evident that specific metabolic pathways are associated with the phenotype of several immune cell types and, importantly, are crucial in controlling their differentiation, proliferation, and effector functions, thus shaping the immune response against pathogens and tumors. In this context, data generated over the last decade have uncovered mammalian sirtuins as important regulators of cellular metabolism, immune cell function, and cancer. Here, we summarize our current knowledge on the roles of this family of protein deacylases on the metabolic control of immune cells and their implications on immune-related diseases and cancer.
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Jakoube P, Cutano V, González-Morena JM, Keckesova Z. Mitochondrial Tumor Suppressors-The Energetic Enemies of Tumor Progression. Cancer Res 2021; 81:4652-4667. [PMID: 34183354 PMCID: PMC9397617 DOI: 10.1158/0008-5472.can-21-0518] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 06/09/2021] [Accepted: 06/24/2021] [Indexed: 01/07/2023]
Abstract
Tumor suppressors represent a critical line of defense against tumorigenesis. Their mechanisms of action and the pathways they are involved in provide important insights into cancer progression, vulnerabilities, and treatment options. Although nuclear and cytosolic tumor suppressors have been extensively investigated, relatively little is known about tumor suppressors localized within the mitochondria. However, recent research has begun to uncover the roles of these important proteins in suppressing tumorigenesis. Here, we review this newly developing field and summarize available information on mitochondrial tumor suppressors.
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Affiliation(s)
- Pavel Jakoube
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.,Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Valentina Cutano
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Juan M. González-Morena
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic
| | - Zuzana Keckesova
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic.,Corresponding Author: Zuzana Keckesova, Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo Namesti 2, Prague 16000, Czech Republic. Phone: 420-2201-83584; E-mail:
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Denu RA, Hematti P. Optimization of oxidative stress for mesenchymal stromal/stem cell engraftment, function and longevity. Free Radic Biol Med 2021; 167:193-200. [PMID: 33677063 DOI: 10.1016/j.freeradbiomed.2021.02.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/24/2021] [Accepted: 02/26/2021] [Indexed: 12/18/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) are multipotent cells that possess great potential as a cellular therapeutic based on their ability to differentiate to different lineages and to modulate immune responses. However, their potential is limited by their low tissue abundance, and thus the need for robust ex vivo expansion prior to their application. This creates its own issues, namely replicative senescence, which could lead to reduced MSC functionality and negatively impact their engraftment. Ex vivo expansion and MSC aging are associated with greater oxidative stress. Therefore, there is great need to identify strategies to reduce oxidative stress in MSCs. This review summarizes the achievements made to date in addressing oxidative stress in MSCs and speculates about interesting avenues of future investigation to solve this critical problem.
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Affiliation(s)
- Ryan A Denu
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
| | - Peiman Hematti
- Departments of Medicine, Pediatrics, Surgery and Biomedical Engineering, Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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26
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Rehan M, Kurundkar D, Kurundkar AR, Logsdon NJ, Smith SR, Chanda D, Bernard K, Sanders YY, Deshane JS, Dsouza KG, Rangarajan S, Zmijewski JW, Thannickal VJ. Restoration of SIRT3 gene expression by airway delivery resolves age-associated persistent lung fibrosis in mice. ACTA ACUST UNITED AC 2021; 1:205-217. [PMID: 34386777 PMCID: PMC8357317 DOI: 10.1038/s43587-021-00027-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aging is a risk factor for progressive fibrotic disorders involving diverse organ systems, including the lung. Idiopathic pulmonary fibrosis, an age-associated degenerative lung disorder, is characterized by persistence of apoptosis-resistant myofibroblasts. In this report, we demonstrate that sirtuin-3 (SIRT3), a mitochondrial deacetylase, is downregulated in lungs of IPF human subjects and in mice subjected to lung injury. Over-expression of the SIRT3 cDNA via airway delivery restored capacity for fibrosis resolution in aged mice, in association with activation of the forkhead box transcription factor, FoxO3a, in fibroblasts, upregulation of pro-apoptotic members of the Bcl-2 family, and recovery of apoptosis susceptibility. While transforming growth factor-β1 reduced levels of SIRT3 and FoxO3a in lung fibroblasts, cell non-autonomous effects involving macrophage secreted products were necessary for SIRT3-mediated activation of FoxO3a. Together, these findings reveal a novel role of SIRT3 in pro-resolution macrophage functions that restore susceptibility to apoptosis in fibroblasts via a FoxO3a-dependent mechanism.
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Affiliation(s)
- Mohammad Rehan
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Deepali Kurundkar
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Ashish R Kurundkar
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Naomi J Logsdon
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Samuel R Smith
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Diptiman Chanda
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Karen Bernard
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Yan Y Sanders
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jessy S Deshane
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Kevin G Dsouza
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Sunad Rangarajan
- Division of Pulmonary Sciences and Critical Care, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jaroslaw W Zmijewski
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Victor J Thannickal
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
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27
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Kratz EM, Sołkiewicz K, Kubis-Kubiak A, Piwowar A. Sirtuins as Important Factors in Pathological States and the Role of Their Molecular Activity Modulators. Int J Mol Sci 2021; 22:ijms22020630. [PMID: 33435263 PMCID: PMC7827102 DOI: 10.3390/ijms22020630] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 01/04/2021] [Accepted: 01/07/2021] [Indexed: 02/06/2023] Open
Abstract
Sirtuins (SIRTs), enzymes from the family of NAD+-dependent histone deacetylases, play an important role in the functioning of the body at the cellular level and participate in many biochemical processes. The multi-directionality of SIRTs encourages scientists to undertake research aimed at understanding the mechanisms of their action and the influence that SIRTs have on the organism. At the same time, new substances are constantly being sought that can modulate the action of SIRTs. Extensive research on the expression of SIRTs in various pathological conditions suggests that regulation of their activity may have positive results in supporting the treatment of certain metabolic, neurodegenerative or cancer diseases or this connected with oxidative stress. Due to such a wide spectrum of activity, SIRTs may also be a prognostic markers of selected pathological conditions and prove helpful in assessing their progression, especially by modulating their activity. The article presents and discusses the activating or inhibiting impact of individual SIRTs modulators. The review also gathered selected currently available information on the expression of SIRTs in individual disease cases as well as the biological role that SIRTs play in the human organism, also in connection with oxidative stress condition, taking into account the progress of knowledge about SIRTs over the years, with particular reference to the latest research results.
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Affiliation(s)
- Ewa Maria Kratz
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
- Correspondence: ; Tel.: +48-(71)-784-01-52
| | - Katarzyna Sołkiewicz
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Adriana Kubis-Kubiak
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland; (A.K.-K.); (A.P.)
| | - Agnieszka Piwowar
- Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 50-556 Wroclaw, Poland; (A.K.-K.); (A.P.)
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A C21-steroidal derivative suppresses T-cell lymphoma in mice by inhibiting SIRT3 via SAP18-SIN3. Commun Biol 2020; 3:732. [PMID: 33273692 PMCID: PMC7713351 DOI: 10.1038/s42003-020-01458-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 11/02/2020] [Indexed: 01/23/2023] Open
Abstract
The SIN3 repressor complex and the NAD-dependent deacetylase SIRT3 control cell growth, and development as well as malignant transformation. Even then, a little known about cross-talks between these two chromatin modifiers or whether their interaction explored therapeutically. Here we describe the identification of a C21-steroidal derivative compound, 3-O-chloroacetyl-gagamine, A671, which potently suppresses the growth of mouse and human T-cell lymphoma and erythroleukemia in vitro and preclinical models. A671 exerts its anti-neoplastic effects by direct interaction with Histone deacetylase complex subunit SAP18, a component of the SIN3 suppressor complex. This interaction stabilizes and activates SAP18, leading to transcriptional suppression of SIRT3, consequently to inhibition of proliferation and cell death. The resistance of cancer cells to A671 correlated with diminished SAP18 activation and sustained SIRT3 expression. These results uncover the SAP18-SIN3-SIRT3 axis that can be pharmacologically targeted by a C21-steroidal agent to suppress T-cell lymphoma and other malignancies. Gajendran et al. show that a C21-steroidal derivative called A671, 3-O-chloroacetyl-gagamine, suppresses the growth of T-cell lymphoma in mice. They find that A671 activates SAP18 to suppress the transcription of SIRT3, inhibiting cell growth. This study presents a new pharmacological target pathway for T-cell lymphoma.
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29
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Ma C, Sun Y, Pi C, Wang H, Sun H, Yu X, Shi Y, He X. Sirt3 Attenuates Oxidative Stress Damage and Rescues Cellular Senescence in Rat Bone Marrow Mesenchymal Stem Cells by Targeting Superoxide Dismutase 2. Front Cell Dev Biol 2020; 8:599376. [PMID: 33330487 PMCID: PMC7718008 DOI: 10.3389/fcell.2020.599376] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 10/21/2020] [Indexed: 12/12/2022] Open
Abstract
Oxidative stress is one of the main causes of aging. The process of physiological aging is always accompanied by increased levels of endogenous oxidative stress. Exogenous oxidants have contributed to premature cellular senescence. As a deacetylase located in mitochondrial matrix, Sirt3 plays critical roles in mitochondrial energy metabolism, oxidative stress regulation, and cellular senescence. However, it remains unknown whether Sirt3 exerts the analogous role in cellular senescence caused by two different oxidation pathways. In this study, the function of Sirt3 was investigated in age-related natural senescence and H2O2-induced premature senescence of rat bone marrow mesenchymal stem cells (MSCs). Our results showed that Sirt3 expression was significantly decreased in both senescent MSCs, which was concerned with reduced cellular reactive oxygen species (ROS) and aggravated DNA injury. Sirt3 repletion could partly reverse the senescence-associated phenotypic features in natural and premature senescent MSCs. Moreover, Sirt3 replenishment led to the reduction in the levels of cellular ROS by enhancing the expression and activity of superoxide dismutase 2 (SOD2), thus maintaining the balance of intracellular oxidation and antioxidation and ameliorating oxidative stress damage. Altogether, Sirt3 inhibits MSC natural senescence and H2O2-induced premature senescence through alleviating ROS-induced injury and upregulating SOD2 expression and activity. Our research indicates that Sirt3 might contribute to uncovering the novel mechanisms underlying MSC senescence and provide new insights to aging and oxidative stress-related diseases.
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Affiliation(s)
- Cao Ma
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China.,Department of Pathology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yanan Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Chenchen Pi
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China.,The First Hospital, Institute of Immunology, Jilin University, Changchun, China
| | - Huan Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Hui Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xiao Yu
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yingai Shi
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xu He
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
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Abstract
Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1)R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2)R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to "intermediate" 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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31
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NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications. Signal Transduct Target Ther 2020; 5:231. [PMID: 33028807 PMCID: PMC7542157 DOI: 10.1038/s41392-020-00326-0] [Citation(s) in RCA: 288] [Impact Index Per Article: 57.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 08/09/2020] [Accepted: 09/14/2020] [Indexed: 02/08/2023] Open
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) is an essential electron donor in all organisms, and provides the reducing power for anabolic reactions and redox balance. NADPH homeostasis is regulated by varied signaling pathways and several metabolic enzymes that undergo adaptive alteration in cancer cells. The metabolic reprogramming of NADPH renders cancer cells both highly dependent on this metabolic network for antioxidant capacity and more susceptible to oxidative stress. Modulating the unique NADPH homeostasis of cancer cells might be an effective strategy to eliminate these cells. In this review, we summarize the current existing literatures on NADPH homeostasis, including its biological functions, regulatory mechanisms and the corresponding therapeutic interventions in human cancers, providing insights into therapeutic implications of targeting NADPH metabolism and the associated mechanism for cancer therapy.
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Wang S, Zhang J, Deng X, Zhao Y, Xu K. Advances in characterization of SIRT3 deacetylation targets in mitochondrial function. Biochimie 2020; 179:1-13. [PMID: 32898647 DOI: 10.1016/j.biochi.2020.08.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/30/2020] [Accepted: 08/26/2020] [Indexed: 12/18/2022]
Abstract
The homeostasis of mitochondrial functional state is intimately in relation with SIRT3 (sirtuin3). SIRT3, the deacetylase mainly anchored in mitochondria, acts as a modulator of metabolic regulation via manipulating the activity and function of downstream targets at post-translational modification levels. The features of energy sensing and ADP-ribose transference of SIRT3 have also been reported. Recently, accumulating SIRT3-focusing evidences have suggested its complicated role in a series of adverse events such as metabolic disorders, aging-related diseases, coupled with tumors, in which SIRT3 regulates the progress of corresponding biochemical reactions by targeting key mediators. By systematically summarizing the downstream deacetylated proteins of the SIRT3 axis, this review aims to give a comprehensive introduction to the main metabolic pathways and diseases of the molecules involved in acetylation modification, which is expected to provide a direction for further exploration of the pathogenesis and therapeutic targets of the above diseases.
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Affiliation(s)
- Shuhan Wang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Junli Zhang
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaoling Deng
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yajuan Zhao
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Keshu Xu
- Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Wan X, Wang C, Huang Z, Zhou D, Xiang S, Qi Q, Chen X, Arbely E, Liu CY, Du P, Yu W. Cisplatin inhibits SIRT3-deacetylation MTHFD2 to disturb cellular redox balance in colorectal cancer cell. Cell Death Dis 2020; 11:649. [PMID: 32811824 PMCID: PMC7434776 DOI: 10.1038/s41419-020-02825-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 07/27/2020] [Accepted: 07/27/2020] [Indexed: 12/28/2022]
Abstract
The folate-coupled metabolic enzyme MTHFD2 (the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase) confers redox homeostasis and drives cancer cell proliferation and migration. Here, we show that MTHFD2 is hyperacetylated and lysine 88 is the critical acetylated site. SIRT3, the major deacetylase in mitochondria, is responsible for MTHFD2 deacetylation. Interestingly, chemotherapeutic agent cisplatin inhibits expression of SIRT3 to induce acetylation of MTHFD2 in colorectal cancer cells. Cisplatin-induced acetylated K88 MTHFD2 is sufficient to inhibit its enzymatic activity and downregulate NADPH levels in colorectal cancer cells. Ac-K88-MTHFD2 is significantly decreased in human colorectal cancer samples and is inversely correlated with the upregulated expression of SIRT3. Our findings reveal an unknown regulation axis of cisplatin-SIRT3-MTHFD2 in redox homeostasis and suggest a potential therapeutic strategy for cancer treatments by targeting MTHFD2.
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Affiliation(s)
- Xingyou Wan
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Chao Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Zhenyu Huang
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China
| | - Dejian Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Sheng Xiang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Qian Qi
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Xinyuan Chen
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Eyal Arbely
- Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
- The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, 8410501, Israel
| | - Chen-Ying Liu
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China
- Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China
| | - Peng Du
- Department of Colorectal and Anal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
- Shanghai Colorectal Cancer Research Center, Shanghai, 200092, China.
| | - Wei Yu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
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Kenny TC, Craig AJ, Villanueva A, Germain D. Mitohormesis Primes Tumor Invasion and Metastasis. Cell Rep 2020; 27:2292-2303.e6. [PMID: 31116976 PMCID: PMC6579120 DOI: 10.1016/j.celrep.2019.04.095] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 03/19/2019] [Accepted: 04/22/2019] [Indexed: 12/31/2022] Open
Abstract
Moderate mitochondrial stress can lead to persistent activation of cytoprotective mechanisms - a phenomenon termed mitohormesis. Here, we show that mitohormesis primes a subpopulation of cancer cells to basally upregulate mitochondrial stress responses, such as the mitochondrial unfolded protein response (UPRmt) providing an adaptive metastatic advantage. In this subpopulation, UPRmt activation persists in the absence of stress, resulting in reduced oxidative stress indicative of mitohormesis. Mechanistically, we showed that the SIRT3 axis of UPRmt is necessary for invasion and metastasis. In breast cancer patients, a 7-gene UPRmt signature demonstrated that UPRmt-HIGH patients have significantly worse clinical outcomes, including metastasis. Transcriptomic analyses revealed that UPRmt-HIGH patients have expression profiles characterized by metastatic programs and the cytoprotective outcomes of mitohormesis. While mitohormesis is associated with health and longevity in non-pathological settings, these results indicate that it is perniciously used by cancer cells to promote tumor progression.
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Affiliation(s)
- Timothy C Kenny
- Tisch Cancer Institute, Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Amanda J Craig
- Tisch Cancer Institute, Department of Medicine, Division of Liver Diseases, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Augusto Villanueva
- Tisch Cancer Institute, Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Department of Medicine, Division of Liver Diseases, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Doris Germain
- Tisch Cancer Institute, Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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Zhang J, Xiang H, Liu J, Chen Y, He RR, Liu B. Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target. Theranostics 2020; 10:8315-8342. [PMID: 32724473 PMCID: PMC7381741 DOI: 10.7150/thno.45922] [Citation(s) in RCA: 290] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 06/08/2020] [Indexed: 02/05/2023] Open
Abstract
Sirtuin 3 (SIRT3) is one of the most prominent deacetylases that can regulate acetylation levels in mitochondria, which are essential for eukaryotic life and inextricably linked to the metabolism of multiple organs. Hitherto, SIRT3 has been substantiated to be involved in almost all aspects of mitochondrial metabolism and homeostasis, protecting mitochondria from a variety of damage. Accumulating evidence has recently documented that SIRT3 is associated with many types of human diseases, including age-related diseases, cancer, heart disease and metabolic diseases, indicating that SIRT3 can be a potential therapeutic target. Here we focus on summarizing the intricate mechanisms of SIRT3 in human diseases, and recent notable advances in the field of small-molecule activators or inhibitors targeting SIRT3 as well as their potential therapeutic applications for future drug discovery.
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Smolková K, Špačková J, Gotvaldová K, Dvořák A, Křenková A, Hubálek M, Holendová B, Vítek L, Ježek P. SIRT3 and GCN5L regulation of NADP+- and NADPH-driven reactions of mitochondrial isocitrate dehydrogenase IDH2. Sci Rep 2020; 10:8677. [PMID: 32457458 PMCID: PMC7250847 DOI: 10.1038/s41598-020-65351-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 04/29/2020] [Indexed: 12/22/2022] Open
Abstract
Wild type mitochondrial isocitrate dehydrogenase (IDH2) was previously reported to produce oncometabolite 2-hydroxyglutarate (2HG). Besides, mitochondrial deacetylase SIRT3 has been shown to regulate the oxidative function of IDH2. However, regulation of 2HG formation by SIRT3-mediated deacetylation was not investigated yet. We aimed to study mitochondrial IDH2 function in response to acetylation and deacetylation, and focus specifically on 2HG production by IDH2. We used acetylation surrogate mutant of IDH2 K413Q and assayed enzyme kinetics of oxidative decarboxylation of isocitrate, 2HG production by the enzyme, and 2HG production in cells. The purified IDH2 K413Q exhibited lower oxidative reaction rates than IDH2 WT. 2HG production by IDH2 K413Q was largely diminished at the enzymatic and cellular level, and knockdown of SIRT3 also inhibited 2HG production by IDH2. Contrary, the expression of putative mitochondrial acetylase GCN5L likely does not target IDH2. Using mass spectroscopy, we further identified lysine residues within IDH2, which are the substrates of SIRT3. In summary, we demonstrate that 2HG levels arise from non-mutant IDH2 reductive function and decrease with increasing acetylation level. The newly identified lysine residues might apply in regulation of IDH2 function in response to metabolic perturbations occurring in cancer cells, such as glucose-free conditions.
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Affiliation(s)
- Katarína Smolková
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic.
| | - Jitka Špačková
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
| | - Klára Gotvaldová
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
| | - Aleš Dvořák
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Alena Křenková
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB CAS), Prague, Czech Republic
| | - Martin Hubálek
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences (IOCB CAS), Prague, Czech Republic
| | - Blanka Holendová
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
| | - Libor Vítek
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Petr Ježek
- Laboratory of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences (IPHYS CAS), Vídeňská 1083, 14220, Prague, Czech Republic
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Jo H, Park Y, Kim T, Kim J, Lee JS, Kim SY, Chung JI, Ko HY, Pyun JC, Kim KS, Lee M, Yun M. Modulation of SIRT3 expression through CDK4/6 enhances the anti-cancer effect of sorafenib in hepatocellular carcinoma cells. BMC Cancer 2020; 20:332. [PMID: 32306906 PMCID: PMC7168998 DOI: 10.1186/s12885-020-06822-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 04/02/2020] [Indexed: 12/15/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib. However, many patients with HCC show reduced sensitivity to sorafenib during treatment. SIRT3, a member of the mammalian sirtuin family, is a tumor suppressor in certain tumor types. However, only few studies have investigated the effects of SIRT3 on tumor prognosis and sorafenib sensitivity in patients with HCC. Here, we aimed to investigate the correlation between SIRT3 expression and glucose metabolism and proliferation in HCC and discover effective compounds that increase endogenous SIRT3 modulation effect of sorafenib. Methods To determine the correlation between SIRT3 and glucose related proteins, immunostaining was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2). We also employed PD0332991 to modulate the SIRT3 expression in HCC cell and conducted functional assays. Results SIRT3 expression was downregulated in high glycolytic and proliferative HCC cells of human patients, xenograft model and HCC cell lines. Moreover, SIRT3 expression was downregulated after sorafenib treatment, resulting in reduced drug sensitivity in HCC cell lines. To enhance the anti-tumor effect of sorafenib, we employed PD0332991 (CDK4/6-Rb inhibitor) based on the correlation between SIRT3 and phosphorylated retinoblastoma protein in HCC. Notably, combined treatment with sorafenib and PD0332991 showed an enhancement of the anti-tumor effect in HCC cells. Conclusions Our data suggest that the modulation of SIRT3 by CDK4/6 inhibition might be useful for HCC therapy together with sorafenib, which, unfortunately, has limited efficacy and whose use is often associated with drug resistance.
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Affiliation(s)
- Hanhee Jo
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, South Korea.,Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 120-749, South Korea
| | - Yusun Park
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, South Korea
| | - Taehun Kim
- Department of Materials Science and Engineering, Yonsei University, Seoul, South Korea
| | - Jisu Kim
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, South Korea
| | - Jong Sook Lee
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, South Korea
| | - Seon Yoo Kim
- Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 120-749, South Korea
| | - Jee-In Chung
- Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 120-749, South Korea
| | - Hae Yong Ko
- Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 120-749, South Korea
| | - Jae-Chul Pyun
- Department of Materials Science and Engineering, Yonsei University, Seoul, South Korea
| | - Kyung Sik Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Misu Lee
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, South Korea.
| | - Mijin Yun
- Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, 120-749, South Korea.
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Gaál Z, Csernoch L. Impact of Sirtuin Enzymes on the Altered Metabolic Phenotype of Malignantly Transformed Cells. Front Oncol 2020; 10:45. [PMID: 32117717 PMCID: PMC7033489 DOI: 10.3389/fonc.2020.00045] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 01/10/2020] [Indexed: 12/19/2022] Open
Abstract
Sirtuins compose a unique collection of histone deacetylase enzymes that have a wide variety of enzymatic activities and regulate diverse cell functions such as cellular metabolism, longevity and energy homeostasis, mitochondrial function, and biogenesis. Impaired sirtuin functions or alterations of their expression levels may result in several pathological conditions and contribute to the altered metabolic phenotype of malignantly transformed cells in a significant manner. In the twenty-first century, principles of personalized anticancer treatment need to involve not only the evaluation of changes of the genetic material, but also the mapping of epigenetic and metabolic alterations, to both of which the contribution of sirtuin enzymes is fundamental. Since sirtuins are central players in the maintenance of cellular energy and metabolic homeostasis, they are key elements in the development of metabolic transformation of cancer cells referred to as the Warburg effect. Although its most well-known features are enhanced glycolysis and excessive lactate production, Warburg effect has several aspects involving both carbohydrate, lipid, and amino acid metabolism, among which different tumor types have different preferences. Therefore, energy supply of cancer cells can be impaired by a growing number of antimetabolite agents, for which appropriate vectors are strongly needed. However, data are controversial about their tumor suppressor or oncogenic properties, the biological effects of sirtuin enzymes strongly depend on the tissue microenvironment (TME) in which they are expressed. Immune cells are regarded as key players of TME. Sirtuins regulate the survival, activation, metabolism, and mitochondrial function of these cells, therefore, they are not only single elements, but key regulators of the network that determines anticancer immunity. Altered metabolism of tumor cells induces changes in the gene expression pattern of cells in TME, due to altered concentrations of metabolite cofactors of epigenetic modifiers including sirtuins. In summary, epigenetic and metabolic alterations in malignant diseases are influenced by sirtuins in a significant manner, and should be treated in a personalized approach. Since they often develop in early stages of cancer, broad examination of these alterations is required at time of the diagnosis in order to provide a personalized combination of distinct therapeutic agents.
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Affiliation(s)
- Zsuzsanna Gaál
- Institute-Clinic of Pediatrics, Department of Physiology, University of Debrecen, Debrecen, Hungary
| | - László Csernoch
- Department of Physiology, University of Debrecen, Debrecen, Hungary
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Kim YS, Gupta Vallur P, Jones VM, Worley BL, Shimko S, Shin DH, Crawford LC, Chen CW, Aird KM, Abraham T, Shepherd TG, Warrick JI, Lee NY, Phaeton R, Mythreye K, Hempel N. Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells. Oncogene 2020; 39:1619-1633. [PMID: 31723239 PMCID: PMC7036012 DOI: 10.1038/s41388-019-1097-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 10/28/2019] [Accepted: 11/04/2019] [Indexed: 12/20/2022]
Abstract
Tumor cells must alter their antioxidant capacity for maximal metastatic potential. Yet the antioxidant adaptations required for ovarian cancer transcoelomic metastasis, which is the passive dissemination of cells in the peritoneal cavity, remain largely unexplored. Somewhat contradicting the need for oxidant scavenging are previous observations that expression of SIRT3, a nutrient stress sensor and regulator of mitochondrial antioxidant defenses, is often suppressed in many primary tumors. We have discovered that this mitochondrial deacetylase is specifically upregulated in a context-dependent manner in cancer cells. SIRT3 activity and expression transiently increased following ovarian cancer cell detachment and in tumor cells derived from malignant ascites of high-grade serous adenocarcinoma patients. Mechanistically, SIRT3 prevents mitochondrial superoxide surges in detached cells by regulating the manganese superoxide dismutase (SOD2). This mitochondrial stress response is under dual regulation by SIRT3. SIRT3 rapidly increases SOD2 activity as an early adaptation to cellular detachment, which is followed by SIRT3-dependent increases in SOD2 mRNA during sustained anchorage-independence. In addition, SIRT3 inhibits glycolytic capacity in anchorage-independent cells thereby contributing to metabolic changes in response to detachment. While manipulation of SIRT3 expression has few deleterious effects on cancer cells in attached conditions, SIRT3 upregulation and SIRT3-mediated oxidant scavenging are required for anoikis resistance in vitro following matrix detachment, and both SIRT3 and SOD2 are necessary for colonization of the peritoneal cavity in vivo. Our results highlight the novel context-specific, pro-metastatic role of SIRT3 in ovarian cancer.
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Affiliation(s)
- Yeon Soo Kim
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Piyushi Gupta Vallur
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Victoria M Jones
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Beth L Worley
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Sara Shimko
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Dong-Hui Shin
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - LaTaijah C Crawford
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Chi-Wei Chen
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Katherine M Aird
- Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Thomas Abraham
- Department of Neural and Behavioral Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Trevor G Shepherd
- The Mary & John Knight Translational Ovarian Cancer Research Unit, Departments of Obstetrics & Gynecology Oncology and Anatomy & Cell Biology, Western University, London, ON, Canada
| | - Joshua I Warrick
- Department of Pathology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Nam Y Lee
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Rebecca Phaeton
- Department of Obstetrics and Gynecology, and Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA, USA
| | - Karthikeyan Mythreye
- Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA.
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Nadine Hempel
- Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA.
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Heinonen T, Ciarlo E, Rigoni E, Regina J, Le Roy D, Roger T. Dual Deletion of the Sirtuins SIRT2 and SIRT3 Impacts on Metabolism and Inflammatory Responses of Macrophages and Protects From Endotoxemia. Front Immunol 2019; 10:2713. [PMID: 31849939 PMCID: PMC6901967 DOI: 10.3389/fimmu.2019.02713] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 11/05/2019] [Indexed: 12/25/2022] Open
Abstract
Sirtuin 2 (SIRT2) and SIRT3 are cytoplasmic and mitochondrial NAD-dependent deacetylases. SIRT2 and SIRT3 target proteins involved in metabolic, proliferation and inflammation pathways and have been implicated in the pathogenesis of neurodegenerative, metabolic and oncologic disorders. Both pro- and anti-inflammatory effects have been attributed to SIRT2 and SIRT3, and single deficiency in SIRT2 or SIRT3 had minor or no impact on antimicrobial innate immune responses. Here, we generated a SIRT2/3 double deficient mouse line to study the interactions between SIRT2 and SIRT3. SIRT2/3−/− mice developed normally and showed subtle alterations of immune cell populations in the bone marrow, thymus, spleen, blood and peritoneal cavity that contained notably more anti-inflammatory B-1a cells and less NK cells. In vitro, SIRT2/3−/− macrophages favored fatty acid oxidation (FAO) over glycolysis and produced increased levels of both proinflammatory and anti-inflammatory cytokines. In line with metabolic adaptation and increased numbers of peritoneal B-1a cells, SIRT2/3−/− mice were robustly protected from endotoxemia. Yet, SIRT2/3 double deficiency did not modify endotoxin tolerance. Overall, these data suggest that sirtuins can act in concert or compensate each other for certain immune functions, a parameter to be considered for drug development. Moreover, inhibitors targeting multiple sirtuins developed for clinical purposes may be useful to treat inflammatory diseases.
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Affiliation(s)
- Tytti Heinonen
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Eleonora Ciarlo
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Ersilia Rigoni
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jean Regina
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Didier Le Roy
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Thierry Roger
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Costa-Machado LF, Fernandez-Marcos PJ. The sirtuin family in cancer. Cell Cycle 2019; 18:2164-2196. [PMID: 31251117 PMCID: PMC6738532 DOI: 10.1080/15384101.2019.1634953] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/27/2019] [Accepted: 06/14/2019] [Indexed: 01/02/2023] Open
Abstract
Sirtuins are a family of protein deacylases and ADP-ribosyl-transferases, homologs to the yeast SIR2 protein. Seven sirtuin paralogs have been described in mammals, with different subcellular locations, targets, enzymatic activities, and regulatory mechanisms. All sirtuins share NAD+ as substrate, placing them as central metabolic hubs with strong relevance in lifespan, metabolism, and cancer development. Much effort has been devoted to studying the roles of sirtuins in cancer, providing a wealth of data on sirtuins roles in mouse models and humans. Also, extensive data are available on the effects of pharmacological modulation of sirtuins in cancer development. Here, we present a comprehensive and organized resume of all the existing evidence linking every sirtuin with cancer development. From our analysis, we conclude that sirtuin modulation after tumor initiation results in unpredictable outcomes in most tumor types. On the contrary, all genetic and pharmacological models indicate that sirtuins activation prior to tumor initiation can constitute a powerful preventive strategy.
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Affiliation(s)
- Luis Filipe Costa-Machado
- Metabolic Syndrome group - BIOPROMET, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain
| | - Pablo J. Fernandez-Marcos
- Metabolic Syndrome group - BIOPROMET, Madrid Institute for Advanced Studies - IMDEA Food, CEI UAM+CSIC, Madrid, Spain
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Patra S, Panigrahi DP, Praharaj PP, Bhol CS, Mahapatra KK, Mishra SR, Behera BP, Jena M, Bhutia SK. Dysregulation of histone deacetylases in carcinogenesis and tumor progression: a possible link to apoptosis and autophagy. Cell Mol Life Sci 2019; 76:3263-3282. [PMID: 30982077 PMCID: PMC11105585 DOI: 10.1007/s00018-019-03098-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/25/2019] [Accepted: 04/08/2019] [Indexed: 02/08/2023]
Abstract
Dysregulation of the epigenome and constitutional epimutation lead to aberrant expression of the genes, which regulate cancer initiation and progression. Histone deacetylases (HDACs), which are highly conserved in yeast to humans, are known to regulate numerous proteins involved in the transcriptional regulation of chromatin structures, apoptosis, autophagy, and mitophagy. In addition, a non-permissive chromatin conformation is created by HDACs, preventing the transcription of the genes encoding the proteins associated with tumorigenesis. Recently, an expanding perspective has been reported from the clinical trials with HDACis (HDAC inhibitors), which has emerged as a determining target for the study of the detailed mechanisms underlying cancer progression. Therefore, the present review focuses on the comprehensive lucubration of post-translational modifications and the molecular mechanisms through which HDACs alter the ambiguities associated with epigenome, with particular insights into the initiation, progression, and regulation of cancer.
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Affiliation(s)
- Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Debasna P Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Prakash P Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Chandra S Bhol
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Kewal K Mahapatra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Soumya R Mishra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Bishnu P Behera
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India
| | - Mrutyunjay Jena
- PG Department of Botany, Berhampur University, Brahmapur, 760007, India
| | - Sujit K Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, Odisha, 769008, India.
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Hypoxia-Inducible Factors as an Alternative Source of Treatment Strategy for Cancer. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8547846. [PMID: 31485300 PMCID: PMC6710762 DOI: 10.1155/2019/8547846] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/13/2019] [Accepted: 07/30/2019] [Indexed: 02/07/2023]
Abstract
Hypoxia-inducible factors (HIFs) are transcription factors that activate the transcription of genes necessary to circumvent to hypoxic (low oxygen level) environments. In carcinogenesis, HIFs play a critical role. Indeed, HIF-1α has been validated as a promising target for novel cancer therapeutics, even as clinical investigations have linked increased levels of HIF-1α with aggressive cancer progression as well as poor patient prognosis. More so, inhibiting HIF-1 activity restricted cancer progression. Therefore, HIF-1 is a viable target for cancer therapy. This may be expected considering the fact that cancer cells are known to be hypoxic. In order to survive the hypoxic microenvironment, cancer cells activate several biochemical pathways via the HIF-1α. Additionally, cellular and molecular insights have proved prospects of the HIF-1α pathway for the development of novel anticancer treatment strategies. The biochemical importance of hypoxia-inducible factors (HIFs) cannot be overemphasized as carcinogenesis, cancer progression, and HIFs are intricately linked. Therefore, this review highlights the significance of these linkages and also the prospects of HIFs as an alternative source of cancer therapies.
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Itami N, Shirasuna K, Kuwayama T, Iwata H. Palmitic acid induces ceramide accumulation, mitochondrial protein hyperacetylation, and mitochondrial dysfunction in porcine oocytes. Biol Reprod 2019; 98:644-653. [PMID: 29385411 DOI: 10.1093/biolre/ioy023] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 01/25/2018] [Indexed: 11/13/2022] Open
Abstract
Low oocyte quality is a possible causal factor of obesity-induced infertility. High palmitic acid (PA) concentration in follicular fluid is a crucial feature noted in obese women. This study examined how high PA concentration reduced mitochondrial quality in oocytes and investigated a possible countermeasure against mitochondrial dysfunction. Cumulus cell-oocyte complexes were obtained from the ovaries of gilts, and incubated in medium containing PA (0.5 mM) or vehicle (BSA) for 44 h. Culturing oocytes at high PA concentration induced mitochondrial dysfunction determined by high reactive oxygen species and low ATP content in oocytes. Furthermore, high PA levels increased mitochondrial acetylation levels determined by a high degree of co-localization of TOMM20 and acetylated-lysine. In addition, high PA levels reduced the expression of Sirtuin 3 (SIRT3) and phosphorylated AMP-activated protein kinase (AMPK), while the AMPK activator, AICAR, restored mitochondrial function as well as oocyte ability and reduced the acetylation of mitochondrial protein. Supplementation of culture medium with dorsomorphin dihydrochloride (an AMPK inhibitor) reduced mitochondrial function and increased mitochondrial protein acetylation. Treatment of oocytes with LB100 (an inhibitor of AMPK dephosphorylation) reduced mitochondrial acetylation levels and restored mitochondrial function. Furthermore, high PA levels increased ceramide accumulation in oocytes, and addition of ceramide to the culture medium also induced mitochondrial dysfunction and increased mitochondrial acetylation. This detrimental effect of ceramide was diminished by AICAR treatment of oocytes. Our results indicated that PA induces ceramide accumulation and downregulates the AMPK/SIRT3 pathway causing mitochondrial protein hyperacetylation and dysfunction in oocytes.
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Affiliation(s)
- Nobuhiko Itami
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Funako, Atsugi, Kanagawa, Japan
| | - Koumei Shirasuna
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Funako, Atsugi, Kanagawa, Japan
| | - Takehito Kuwayama
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Funako, Atsugi, Kanagawa, Japan
| | - Hisataka Iwata
- Laboratory of Animal Reproduction, Department of Animal Science, Tokyo University of Agriculture, Funako, Atsugi, Kanagawa, Japan
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Li M, Chiang YL, Lyssiotis CA, Teater MR, Hong JY, Shen H, Wang L, Hu J, Jing H, Chen Z, Jain N, Duy C, Mistry SJ, Cerchietti L, Cross JR, Cantley LC, Green MR, Lin H, Melnick AM. Non-oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis. Cancer Cell 2019; 35:916-931.e9. [PMID: 31185214 PMCID: PMC7534582 DOI: 10.1016/j.ccell.2019.05.002] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 02/05/2019] [Accepted: 05/07/2019] [Indexed: 12/14/2022]
Abstract
Diffuse large B cell lymphomas (DLBCLs) are genetically heterogeneous and highly proliferative neoplasms derived from germinal center (GC) B cells. Here, we show that DLBCLs are dependent on mitochondrial lysine deacetylase SIRT3 for proliferation, survival, self-renewal, and tumor growth in vivo regardless of disease subtype and genetics. SIRT3 knockout attenuated B cell lymphomagenesis in VavP-Bcl2 mice without affecting normal GC formation. Mechanistically, SIRT3 depletion impaired glutamine flux to the TCA cycle via glutamate dehydrogenase and reduction in acetyl-CoA pools, which in turn induce autophagy and cell death. We developed a mitochondrial-targeted class I sirtuin inhibitor, YC8-02, which phenocopied the effects of SIRT3 depletion and killed DLBCL cells. SIRT3 is thus a metabolic non-oncogene addiction and therapeutic target for DLBCLs.
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MESH Headings
- Acetyl Coenzyme A/metabolism
- Animals
- Antineoplastic Agents/pharmacology
- Autophagic Cell Death/drug effects
- Cell Proliferation/drug effects
- Citric Acid Cycle/drug effects
- Energy Metabolism/drug effects
- Female
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Glutamine/metabolism
- HEK293 Cells
- Histone Deacetylase Inhibitors/pharmacology
- Humans
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/enzymology
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/pathology
- MCF-7 Cells
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Knockout
- Mice, SCID
- Molecular Targeted Therapy
- Signal Transduction
- Sirtuin 3/antagonists & inhibitors
- Sirtuin 3/deficiency
- Sirtuin 3/genetics
- Sirtuin 3/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Meng Li
- Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ying-Ling Chiang
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Matthew R Teater
- Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Jun Young Hong
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Hao Shen
- Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ling Wang
- Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Jing Hu
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Hui Jing
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA
| | - Zhengming Chen
- Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, NY 10021, USA
| | - Neeraj Jain
- Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77005, USA
| | - Cihangir Duy
- Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Sucharita J Mistry
- Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Leandro Cerchietti
- Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Justin R Cross
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Lewis C Cantley
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Michael R Green
- Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77005, USA
| | - Hening Lin
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Howard Hughes Medical Institute; Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
| | - Ari M Melnick
- Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY 10065, USA.
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Li J, Yue H, Yu H, Lu X, Xue X. Development and validation of SIRT3-related nomogram predictive of overall survival in patients with serous ovarian cancer. J Ovarian Res 2019; 12:47. [PMID: 31113446 PMCID: PMC6530022 DOI: 10.1186/s13048-019-0524-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 05/13/2019] [Indexed: 01/10/2023] Open
Abstract
Objective Our aim is to analyzed the expression pattern of sirtuin(SIRT) superfamily and evaluated their prognostic values in serous ovarian cancer patients. Methods We first analyzed the differential expression of SIRT members among fallopian tube epithelium (FTE), primary serous ovarian cancers/tubal cancers (PSOCs/PSTCs), and omental metastases using GSE10971 and GSE30587 datasets. The prognostic values of SIRT members were evaluated using TCGA and GSE9891 dataset. Results SIRT3 and SIRT5 expression were significantly decreased and increased in PSOCs/PSTCs compared with that in normal counterparts, respectively. SIRT6 and SIRT7 were overexpressed in ometal metastases compared with corresponding primary counterparts. With respect to recurrence free survival, however, SIRT7 overexpression was correlated with better prognosis. A similar trend was observed by multivariable analysis. Regarding overall survival (OS), increased expression of SIRT3, SIRT5, and SIRT7 were associated with better survival by univariable analysis. Subsequent multivariable analysis showed that SIRT3 remained an independent favorable prognostic factor for OS. The SIRT3-related nomogram illustrated age at initial diagnosis as sharing the largest contribution to OS, followed by SIRT3 expression and FIGO stage. The C-index for OS prediction was 0.65 (95%CI, 0.61–0.69) in training cohort (TCGA dataset) and 0.65 (95%CI, 0.59–0.71) in validation cohort (GSE9891 dataset), respectively. The calibration plots showed optimal agreement between the prediction by SIRT3-related nomogram and actual observation for 1-, 3-, and 5-year OS probability. Conclusion In conclusion, SIRT3 was an independent favorable prognostic factor for OS in serous ovarian cancer, and added prognostic value to the traditional clinicopathological factors used to evaluate patients’ prognosis.
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Affiliation(s)
- Jun Li
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Huiran Yue
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Hailin Yu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Xin Lu
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Xiaohong Xue
- Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, No.419, Fangxie Road, Shanghai, 200011, China. .,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China.
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Wild-Type IDH Enzymes as Actionable Targets for Cancer Therapy. Cancers (Basel) 2019; 11:cancers11040563. [PMID: 31010244 PMCID: PMC6520797 DOI: 10.3390/cancers11040563] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/12/2019] [Accepted: 04/16/2019] [Indexed: 12/11/2022] Open
Abstract
Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (αKG) and CO2. The discovery of IDH1 and IDH2 mutations in several malignancies has brought to the approval of drugs targeting IDH1/2 mutants in cancers. Here, we summarized findings addressing the impact of IDH mutants in rare pathologies and focused on the relevance of non-mutated IDH enzymes in tumors. Several pieces of evidence suggest that the enzymatic inhibition of IDHs may have therapeutic potentials also in wild-type IDH cancers. Moreover, IDHs inhibition could enhance the efficacy of canonical cancer therapies, such as chemotherapy, target therapy, and radiotherapy. However, further studies are required to elucidate whether IDH proteins are diagnostic/prognostic markers, instrumental for tumor initiation and maintenance, and could be exploited as targets for anticancer therapy. The development of wild-type IDH inhibitors is expected to improve our understanding of a potential non-oncogenic addition to IDH1/2 activities and to fully address their applicability in combination with other therapies.
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Ghirotto B, Terra FF, Câmara NOS, Basso PJ. Sirtuins in B lymphocytes metabolism and function. World J Exp Med 2019; 9:1-13. [PMID: 30705866 PMCID: PMC6354076 DOI: 10.5493/wjem.v9.i1.1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/29/2018] [Accepted: 01/05/2019] [Indexed: 02/06/2023] Open
Abstract
Sirtuins (SIRTs) are NAD+-dependent histone deacetylases and play a role in virtually all cell biological processes. As SIRTs functions vary according to their subtypes, they can either activate or inhibit signaling pathways upon different conditions or tissues. Recent studies have focused on metabolic effects performed by SIRTs in several cell types since specific metabolic pathways (e.g., aerobic glycolysis, oxidative phosphorylation, β-oxidation, glutaminolysis) are used to determine the cell fate. However, few efforts have been made to understand the role of SIRTs on B lymphocytes metabolism and function. These cells are associated with humoral immune responses by secreting larger amounts of antibodies after differentiating into antibody-secreting cells. Besides, both the SIRTs and B lymphocytes are potential targets to treat several immune-mediated disorders, including cancer. Here, we provide an outlook of recent studies regarding the role of SIRTs in general cellular metabolism and B lymphocytes functions, pointing out the future perspectives of this field.
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Affiliation(s)
- Bruno Ghirotto
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
| | - Fernanda Fernandes Terra
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
| | - Niels Olsen Saraiva Câmara
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
- Division of Nephrology, School of Medicine, Federal University of São Paulo, São Paulo 04023-062, Brazil
- Laboratory of Renal Physiology (LIM 16), School of Medicine, University of São Paulo, São Paulo 01246-903, Brazil
| | - Paulo José Basso
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil
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49
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Warren JL, MacIver NJ. Regulation of Adaptive Immune Cells by Sirtuins. Front Endocrinol (Lausanne) 2019; 10:466. [PMID: 31354630 PMCID: PMC6637536 DOI: 10.3389/fendo.2019.00466] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 06/26/2019] [Indexed: 12/16/2022] Open
Abstract
It is now well-established that the pathways that control lymphocyte metabolism and function are intimately linked, and changes in lymphocyte metabolism can influence and direct cellular function. Interestingly, a number of recent advances indicate that lymphocyte identity and metabolism is partially controlled via epigenetic regulation. Epigenetic mechanisms, such as changes in DNA methylation or histone acetylation, have been found to alter immune function and play a role in numerous chronic disease states. There are several enzymes that can mediate epigenetic changes; of particular interest are sirtuins, protein deacetylases that mediate adaptive responses to a variety of stresses (including calorie restriction and metabolic stress) and are now understood to play a significant role in immunity. This review will focus on recent advances in the understanding of how sirtuins affect the adaptive immune system. These pathways are of significant interest as therapeutic targets for the treatment of autoimmunity, cancer, and transplant tolerance.
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Affiliation(s)
- Jonathan L. Warren
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States
| | - Nancie J. MacIver
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States
- Department of Immunology, Duke University School of Medicine, Durham, NC, United States
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, United States
- *Correspondence: Nancie J. MacIver
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50
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Chaiswing L, St. Clair WH, St. Clair DK. Redox Paradox: A Novel Approach to Therapeutics-Resistant Cancer. Antioxid Redox Signal 2018; 29:1237-1272. [PMID: 29325444 PMCID: PMC6157438 DOI: 10.1089/ars.2017.7485] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 01/05/2018] [Indexed: 02/06/2023]
Abstract
SIGNIFICANCE Cancer cells that are resistant to radiation and chemotherapy are a major problem limiting the success of cancer therapy. Aggressive cancer cells depend on elevated intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and metastasize. As a result, these aggressive cancers maintain high basal levels of ROS compared with normal cells. The prominence of the redox state in cancer cells led us to consider whether increasing the redox state to the condition of oxidative stress could be used as a successful adjuvant therapy for aggressive cancers. Recent Advances: Past attempts using antioxidant compounds to inhibit ROS levels in cancers as redox-based therapy have met with very limited success. However, recent clinical trials using pro-oxidant compounds reveal noteworthy results, which could have a significant impact on the development of strategies for redox-based therapies. CRITICAL ISSUES The major objective of this review is to discuss the role of the redox state in aggressive cancers and how to utilize the shift in redox state to improve cancer therapy. We also discuss the paradox of redox state parameters; that is, hydrogen peroxide (H2O2) as the driver molecule for cancer progression as well as a target for cancer treatment. FUTURE DIRECTIONS Based on the biological significance of the redox state, we postulate that this system could potentially be used to create a new avenue for targeted therapy, including the potential to incorporate personalized redox therapy for cancer treatment.
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Affiliation(s)
- Luksana Chaiswing
- Department of Toxicology and Cancer Biology, University of Kentucky-Lexington, Lexington, Kentucky
| | - William H. St. Clair
- Department of Radiation Medicine, University of Kentucky-Lexington, Lexington, Kentucky
| | - Daret K. St. Clair
- Department of Toxicology and Cancer Biology, University of Kentucky-Lexington, Lexington, Kentucky
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