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Fiorentino F, Fabbrizi E, Mai A, Rotili D. Activation and inhibition of sirtuins: From bench to bedside. Med Res Rev 2025; 45:484-560. [PMID: 39215785 PMCID: PMC11796339 DOI: 10.1002/med.22076] [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: 05/25/2022] [Revised: 07/27/2024] [Accepted: 08/04/2024] [Indexed: 09/04/2024]
Abstract
The sirtuin family comprises seven NAD+-dependent enzymes which catalyze protein lysine deacylation and mono ADP-ribosylation. Sirtuins act as central regulators of genomic stability and gene expression and control key processes, including energetic metabolism, cell cycle, differentiation, apoptosis, and aging. As a result, all sirtuins play critical roles in cellular homeostasis and organism wellness, and their dysregulation has been linked to metabolic, cardiovascular, and neurological diseases. Furthermore, sirtuins have shown dichotomous roles in cancer, acting as context-dependent tumor suppressors or promoters. Given their central role in different cellular processes, sirtuins have attracted increasing research interest aimed at developing both activators and inhibitors. Indeed, sirtuin modulation may have therapeutic effects in many age-related diseases, including diabetes, cardiovascular and neurodegenerative disorders, and cancer. Moreover, isoform selective modulators may increase our knowledge of sirtuin biology and aid to develop better therapies. Through this review, we provide critical insights into sirtuin pharmacology and illustrate their enzymatic activities and biological functions. Furthermore, we outline the most relevant sirtuin modulators in terms of their modes of action, structure-activity relationships, pharmacological effects, and clinical applications.
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Affiliation(s)
- Francesco Fiorentino
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Emanuele Fabbrizi
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
| | - Antonello Mai
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
- Pasteur Institute, Cenci‐Bolognetti FoundationSapienza University of RomeRomeItaly
| | - Dante Rotili
- Department of Drug Chemistry and TechnologiesSapienza University of RomeRomeItaly
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2
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Tharayil JS, Kandettu A, Chakrabarty S. The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll? Biochim Biophys Acta Mol Basis Dis 2025; 1871:167691. [PMID: 39864670 DOI: 10.1016/j.bbadis.2025.167691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 01/08/2025] [Accepted: 01/21/2025] [Indexed: 01/28/2025]
Abstract
Mammalian sirtuins are class III histone deacetylases involved in the regulation of multiple biological processes including senescence, DNA repair, apoptosis, proliferation, caloric restriction, and metabolism. Among the mammalian sirtuins, SIRT3, SIRT4, and SIRT5 are localized in the mitochondria and collectively termed the mitochondrial sirtuins. Mitochondrial sirtuins are NAD+-dependent deacetylases that play a central role in cellular metabolism and function as epigenetic regulators by performing post-translational modification of cellular proteins. Several studies have identified the role of mitochondrial sirtuins in age-related pathologies and the rewiring of cancer metabolism. Mitochondrial sirtuins regulate cellular functions by contributing to post-translational modifications, including deacetylation, ADP-ribosylation, demalonylation, and desuccinylation of diverse cellular proteins to maintain cellular homeostasis. Here, we review and discuss the structure and function of the mitochondrial sirtuins and their role as metabolic regulators in breast cancer. Altered breast cancer metabolism may promote tumor progression and has been an essential target for therapy. Further, we discuss the potential role of targeting mitochondrial sirtuin and its impact on breast cancer progression using sirtuin inhibitors and activators as anticancer agents.
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Affiliation(s)
- Jesline Shaji Tharayil
- Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS), Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Amoolya Kandettu
- Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS), Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Sanjiban Chakrabarty
- Department of Public Health Genomics, Centre for DNA Repair and Genome Stability (CDRGS), Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
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3
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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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Spallotta F, Illi B. The Role of HDAC6 in Glioblastoma Multiforme: A New Avenue to Therapeutic Interventions? Biomedicines 2024; 12:2631. [PMID: 39595195 PMCID: PMC11591585 DOI: 10.3390/biomedicines12112631] [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: 10/31/2024] [Revised: 11/14/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Despite the great advances in basic research results, glioblastoma multiforme (GBM) still remains an incurable tumour. To date, a GBM diagnosis is a death sentence within 15-18 months, due to the high recurrence rate and resistance to conventional radio- and chemotherapy approaches. The effort the scientific community is lavishing on the never-ending battle against GBM is reflected by the huge number of clinical trials launched, about 2003 on 10 September 2024. However, we are still far from both an in-depth comprehension of the biological and molecular processes leading to GBM onset and progression and, importantly, a cure. GBM is provided with high intratumoral heterogeneity, immunosuppressive capacity, and infiltrative ability due to neoangiogenesis. These features impact both tumour aggressiveness and therapeutic vulnerability, which is further limited by the presence in the tumour core of niches of glioblastoma stem cells (GSCs) that are responsible for the relapse of this brain neoplasm. Epigenetic alterations may both drive and develop along GBM progression and also rely on changes in the expression of the genes encoding histone-modifying enzymes, including histone deacetylases (HDACs). Among them, HDAC6-a cytoplasmic HDAC-has recently gained attention because of its role in modulating several biological aspects of GBM, including DNA repair ability, massive growth, radio- and chemoresistance, and de-differentiation through primary cilia disruption. In this review article, the available information related to HDAC6 function in GBM will be presented, with the aim of proposing its inhibition as a valuable therapeutic route for this deadly brain tumour.
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Affiliation(s)
- Francesco Spallotta
- Department of Biology and Biotechnology Charles Darwin, Sapienza University, 00185 Rome, Italy;
- Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, 00185 Rome, Italy
| | - Barbara Illi
- Institute of Molecular Biology and Pathology, National Research Council (IBPM-CNR), 00185 Rome, Italy
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5
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Minisini M, Cricchi E, Brancolini C. Acetylation and Phosphorylation in the Regulation of Hypoxia-Inducible Factor Activities: Additional Options to Modulate Adaptations to Changes in Oxygen Levels. Life (Basel) 2023; 14:20. [PMID: 38276269 PMCID: PMC10821055 DOI: 10.3390/life14010020] [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: 12/05/2023] [Revised: 12/13/2023] [Accepted: 12/20/2023] [Indexed: 01/27/2024] Open
Abstract
O2 is essential for the life of eukaryotic cells. The ability to sense oxygen availability and initiate a response to adapt the cell to changes in O2 levels is a fundamental achievement of evolution. The key switch for adaptation consists of the transcription factors HIF1A, HIF2A and HIF3A. Their levels are tightly controlled by O2 through the involvement of the oxygen-dependent prolyl hydroxylase domain-containing enzymes (PHDs/EGNLs), the von Hippel-Lindau tumour suppressor protein (pVHL) and the ubiquitin-proteasome system. Furthermore, HIF1A and HIF2A are also under the control of additional post-translational modifications (PTMs) that positively or negatively regulate the activities of these transcription factors. This review focuses mainly on two PTMs of HIF1A and HIF2A: phosphorylation and acetylation.
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Affiliation(s)
| | | | - Claudio Brancolini
- Lab of Epigenomics, Department of Medicine, Università degli Studi di Udine, 33100 Udine, Italy; (M.M.); (E.C.)
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6
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Hampel N, Georgy J, Mehrabipour M, Lang A, Lehmkuhl I, Scheller J, Ahmadian MR, Floss DM, Piekorz RP. CoCl 2 -triggered pseudohypoxic stress induces proteasomal degradation of SIRT4 via polyubiquitination of lysines K78 and K299. FEBS Open Bio 2023; 13:2187-2199. [PMID: 37803520 PMCID: PMC10699113 DOI: 10.1002/2211-5463.13715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 08/24/2023] [Accepted: 10/04/2023] [Indexed: 10/08/2023] Open
Abstract
SIRT4, together with SIRT3 and SIRT5, comprises the mitochondrially localized subgroup of sirtuins. SIRT4 regulates mitochondrial bioenergetics, dynamics (mitochondrial fusion), and quality control (mitophagy) via its NAD+ -dependent enzymatic activities. Here, we address the regulation of SIRT4 itself by characterizing its protein stability and degradation upon CoCl2 -induced pseudohypoxic stress that typically triggers mitophagy. Interestingly, we observed that of the mitochondrial sirtuins, only the protein levels of SIRT4 or ectopically expressed SIRT4-eGFP decrease upon CoCl2 treatment of HEK293 cells. Co-treatment with BafA1, an inhibitor of autophagosome-lysosome fusion required for autophagy/mitophagy, or the use of the proteasome inhibitor MG132, prevented CoCl2 -induced SIRT4 downregulation. Consistent with the proteasomal degradation of SIRT4, the lysine mutants SIRT4(K78R) and SIRT4(K299R) showed significantly reduced polyubiquitination upon CoCl2 treatment and were more resistant to pseudohypoxia-induced degradation as compared to SIRT4. Moreover, SIRT4(K78R) and SIRT4(K299R) displayed increased basal protein stability as compared to wild-type SIRT4 when subjected to MG132 treatment or cycloheximide (CHX) chase assays. Thus, our data indicate that stress-induced protein degradation of SIRT4 occurs through two mechanisms: (a) via mitochondrial autophagy/mitophagy, and (b) as a separate process via proteasomal degradation within the cytoplasm.
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Affiliation(s)
- Nils Hampel
- Institute of Biochemistry and Molecular Biology II, Medical FacultyHeinrich Heine University DüsseldorfUniversitätsstrasse 1Düsseldorf40225Germany
| | - Jacqueline Georgy
- Institute of Biochemistry and Molecular Biology II, Medical FacultyHeinrich Heine University DüsseldorfUniversitätsstrasse 1Düsseldorf40225Germany
| | - Mehrnaz Mehrabipour
- Institute of Biochemistry and Molecular Biology II, Medical FacultyHeinrich Heine University DüsseldorfUniversitätsstrasse 1Düsseldorf40225Germany
| | - Alexander Lang
- Institute of Biochemistry and Molecular Biology II, Medical FacultyHeinrich Heine University DüsseldorfUniversitätsstrasse 1Düsseldorf40225Germany
- Present address:
Department of Cardiology, Pulmonology, and Vascular Medicine, Medical FacultyHeinrich Heine University DüsseldorfGermany
| | - Isabell Lehmkuhl
- Institute of Biochemistry and Molecular Biology II, Medical FacultyHeinrich Heine University DüsseldorfUniversitätsstrasse 1Düsseldorf40225Germany
| | - Jürgen Scheller
- Institute of Biochemistry and Molecular Biology II, Medical FacultyHeinrich Heine University DüsseldorfUniversitätsstrasse 1Düsseldorf40225Germany
| | - Mohammad R. Ahmadian
- Institute of Biochemistry and Molecular Biology II, Medical FacultyHeinrich Heine University DüsseldorfUniversitätsstrasse 1Düsseldorf40225Germany
| | - Doreen M. Floss
- Institute of Biochemistry and Molecular Biology II, Medical FacultyHeinrich Heine University DüsseldorfUniversitätsstrasse 1Düsseldorf40225Germany
| | - Roland P. Piekorz
- Institute of Biochemistry and Molecular Biology II, Medical FacultyHeinrich Heine University DüsseldorfUniversitätsstrasse 1Düsseldorf40225Germany
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7
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Kanwore K, Kanwore K, Guo X, Xia Y, Zhou H, Zhang L, Adzika GK, Joseph AA, Abiola AA, Mu P, Kambey PA, Noah MLN, Gao D. Testosterone upregulates glial cell line-derived neurotrophic factor (GDNF) and promotes neuroinflammation to enhance glioma cell survival and proliferation. Inflamm Regen 2023; 43:49. [PMID: 37833789 PMCID: PMC10571473 DOI: 10.1186/s41232-023-00300-7] [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: 05/10/2023] [Accepted: 09/28/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Testosterone contributes to male organism development, such as bone density, muscle development, and fat repartition. Estrogen (derived from testosterone) also contributes to female reproductive system development. Here, we investigated the effect of testosterone on glioma cells and brain neuron inflammation essential for cancer development and progression. METHODS The human astrocyte and glioma cell lines were treated with 6 ng/ml exogenous testosterone in vitro. We performed cell counting kit-8, transwell, and wound healing assays to determine the effect of testosterone on glioma cell proliferation, migration, and invasion. The glioma cells were injected into the xenograft and treated with 5 µl concentrated testosterone. Transcriptional suppression of glial cell line-derived neurotrophic factor (GDNF) was performed to evaluate brain neuron inflammation and survival. The tumor tissues were assessed by hematoxylin-eosin staining and immunohistochemistry. RESULTS Testosterone upregulates GDNF to stimulate proliferation, migration, and invasion of glioma cells. Pathologically, the augmentation of GDNF and cyclophilin A contributed to neuroprotection when treated with testosterone. Our investigation showed that testosterone contributes to brain neuron and astrocyte inflammation through the upregulation of nuclear factor erythroid 2-related factor 2 (NRF2), glial fibrillary acid protein (GFAP), and sirtuin 5 (SIRT5), resulting in pro-inflammatory macrophages recruitments into the neural microenvironment. Mechanically, testosterone treatment regulates GDNF translocation from the glioma cells and astrocyte nuclei to the cytoplasm. CONCLUSION Testosterone upregulates GDNF in glioma cells and astrocytes essential for microglial proliferation, migration, and invasion. Testosterone contributes to brain tumor growth via GDNF and inflammation. The contribution of testosterone, macrophages, and astrocytes, in old neuron rescue, survival, and proliferation. During brain neuron inflammation, the organism activates and stimulates the neuron rescue through the enrichment of the old neuron microenvironment with growth factors such as GDNF, BDNF, SOX1/2, and MAPK secreted by the surrounding neurons and glial cells to maintain the damaged neuron by inflammation alive even if the axon is dead. The immune response also contributes to brain cell survival through the secretion of proinflammatory cytokines, resulting in inflammation maintenance. The rescued old neuron interaction with infiltrated macrophages contributes to angiogenesis to supplement the old neuron with more nutrients leading to metabolism activation and surrounding cell uncontrollable cell growth.
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Affiliation(s)
- Kouminin Kanwore
- Public Experimental Research Center, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
| | - Konimpo Kanwore
- Mixed Faculty of Medicine and Pharmacy, University of Lomé, Lomé, Togo
| | - Xiaoxiao Guo
- Public Experimental Research Center, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Ying Xia
- Public Experimental Research Center, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Han Zhou
- Public Experimental Research Center, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Lin Zhang
- Public Experimental Research Center, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | | | | | - Ayanlaja Abdulrahman Abiola
- Public Experimental Research Center, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Peipei Mu
- Public Experimental Research Center, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Piniel Alphayo Kambey
- Public Experimental Research Center, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | | | - DianShuai Gao
- Public Experimental Research Center, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
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8
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Arévalo CM, Cruz-Rodriguez N, Quijano S, Fiorentino S. Plant-derived extracts and metabolic modulation in leukemia: a promising approach to overcome treatment resistance. Front Mol Biosci 2023; 10:1229760. [PMID: 37520325 PMCID: PMC10382028 DOI: 10.3389/fmolb.2023.1229760] [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: 05/27/2023] [Accepted: 06/30/2023] [Indexed: 08/01/2023] Open
Abstract
Leukemic cells acquire complex and often multifactorial mechanisms of resistance to treatment, including various metabolic alterations. Although the use of metabolic modulators has been proposed for several decades, their use in clinical practice has not been established. Natural products, the so-called botanical drugs, are capable of regulating tumor metabolism, particularly in hematopoietic tumors, which could partly explain the biological activity attributed to them for a long time. This review addresses the most recent findings relating to metabolic reprogramming-Mainly in the glycolytic pathway and mitochondrial activity-Of leukemic cells and its role in the generation of resistance to conventional treatments, the modulation of the tumor microenvironment, and the evasion of immune response. In turn, it describes how the modulation of metabolism by plant-derived extracts can counteract resistance to chemotherapy in this tumor model and contribute to the activation of the antitumor immune system.
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Affiliation(s)
- Cindy Mayerli Arévalo
- Grupo de Inmunobiología y Biología Celular, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | | | - Sandra Quijano
- Grupo de Inmunobiología y Biología Celular, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Susana Fiorentino
- Grupo de Inmunobiología y Biología Celular, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
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Deng J, Liu ZM, Zhu KR, Cui GL, Liu LX, Yan YH, Ning XL, Yu ZJ, Li GB, Qi QR. New ε-N-thioglutaryl-lysine derivatives as SIRT5 inhibitors: Chemical synthesis, kinetic and crystallographic studies. Bioorg Chem 2023; 135:106487. [PMID: 36996510 DOI: 10.1016/j.bioorg.2023.106487] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023]
Abstract
SIRT5 has been implicated in various physiological processes and human diseases, including cancer. Development of new highly potent, selective SIRT5 inhibitors is still needed to investigate disease-related mechanisms and therapeutic potentials. We here report new ε-N-thioglutaryllysine derivatives, which were designed according to SIRT5-catalysed deacylation reactions. These ε-N-thioglutaryllysine derivatives displayed potent SIRT5 inhibition, of which the potential photo-crosslinking derivative 8 manifested most potent inhibition with an IC50 value of 120 nM to SIRT5, and low inhibition to SIRT1-3 and SIRT6. The enzyme kinetic assays revealed that the ε-N-thioglutaryllysine derivatives inhibit SIRT5 by lysine-substrate competitive manner. Co-crystallographic analyses demonstrated that 8 binds to occupy the lysine-substate binding site by making hydrogen-bonding and electrostatic interactions with SIRT5-specific residues, and is likely positioned to react with NAD+ and form stable thio-intermediates. Compound 8 was observed to have low photo-crosslinking probability to SIRT5, possibly due to inappropriate position of the diazirine group as observed in SIRT5:8 crystal structure. This study provides useful information for developing drug-like inhibitors and cross-linking chemical probes for SIRT5-related studies.
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10
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Fabbrizi E, Fiorentino F, Carafa V, Altucci L, Mai A, Rotili D. Emerging Roles of SIRT5 in Metabolism, Cancer, and SARS-CoV-2 Infection. Cells 2023; 12:cells12060852. [PMID: 36980194 PMCID: PMC10047932 DOI: 10.3390/cells12060852] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 03/02/2023] [Accepted: 03/07/2023] [Indexed: 03/12/2023] Open
Abstract
Sirtuin 5 (SIRT5) is a predominantly mitochondrial enzyme catalyzing the removal of glutaryl, succinyl, malonyl, and acetyl groups from lysine residues through a NAD+-dependent deacylase mechanism. SIRT5 is an important regulator of cellular homeostasis and modulates the activity of proteins involved in different metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, fatty acid oxidation, electron transport chain, generation of ketone bodies, nitrogenous waste management, and reactive oxygen species (ROS) detoxification. SIRT5 controls a wide range of aspects of myocardial energy metabolism and plays critical roles in heart physiology and stress responses. Moreover, SIRT5 has a protective function in the context of neurodegenerative diseases, while it acts as a context-dependent tumor promoter or suppressor. In addition, current research has demonstrated that SIRT5 is implicated in the SARS-CoV-2 infection, although opposing conclusions have been drawn in different studies. Here, we review the current knowledge on SIRT5 molecular actions under both healthy and diseased settings, as well as its functional effects on metabolic targets. Finally, we revise the potential of SIRT5 as a therapeutic target and provide an overview of the currently reported SIRT5 modulators, which include both activators and inhibitors.
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Affiliation(s)
- Emanuele Fabbrizi
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Francesco Fiorentino
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
| | - Vincenzo Carafa
- Department of Precision Medicine, Università degli Studi della Campania “L. Vanvitelli”, 80138 Naples, Italy
- BIOGEM, 83031 Ariano Irpino, Italy
| | - Lucia Altucci
- Department of Precision Medicine, Università degli Studi della Campania “L. Vanvitelli”, 80138 Naples, Italy
- BIOGEM, 83031 Ariano Irpino, Italy
- IEOS—Istituto per l’Endocrinologia e Oncologia Sperimentale, CNR, 80131 Naples, Italy
| | - Antonello Mai
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
- Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence: (A.M.); (D.R.); Tel.: +39-0649913392 (A.M.); +39-0649913237 (D.R.); Fax: +39-0649693268 (A.M.)
| | - Dante Rotili
- Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence: (A.M.); (D.R.); Tel.: +39-0649913392 (A.M.); +39-0649913237 (D.R.); Fax: +39-0649693268 (A.M.)
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11
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Ziętara P, Dziewięcka M, Augustyniak M. Why Is Longevity Still a Scientific Mystery? Sirtuins-Past, Present and Future. Int J Mol Sci 2022; 24:728. [PMID: 36614171 PMCID: PMC9821238 DOI: 10.3390/ijms24010728] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/22/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
The sirtuin system consists of seven highly conserved regulatory enzymes responsible for metabolism, antioxidant protection, and cell cycle regulation. The great interest in sirtuins is associated with the potential impact on life extension. This article summarizes the latest research on the activity of sirtuins and their role in the aging process. The effects of compounds that modulate the activity of sirtuins were discussed, and in numerous studies, their effectiveness was demonstrated. Attention was paid to the role of a caloric restriction and the risks associated with the influence of careless sirtuin modulation on the organism. It has been shown that low modulators' bioavailability/retention time is a crucial problem for optimal regulation of the studied pathways. Therefore, a detailed understanding of the modulator structure and potential reactivity with sirtuins in silico studies should precede in vitro and in vivo experiments. The latest achievements in nanobiotechnology make it possible to create promising molecules, but many of them remain in the sphere of plans and concepts. It seems that solving the mystery of longevity will have to wait for new scientific discoveries.
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Affiliation(s)
| | | | - Maria Augustyniak
- Faculty of Natural Sciences, Institute of Biology, Biotechnology and Environmental Protection, University of Silesia in Katowice, ul. Bankowa 9, 40-007 Katowice, Poland
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12
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Liu Y, Chen C, Wang X, Sun Y, Zhang J, Chen J, Shi Y. An Epigenetic Role of Mitochondria in Cancer. Cells 2022; 11:cells11162518. [PMID: 36010594 PMCID: PMC9406960 DOI: 10.3390/cells11162518] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/03/2022] [Accepted: 08/09/2022] [Indexed: 12/14/2022] Open
Abstract
Mitochondria are not only the main energy supplier but are also the cell metabolic center regulating multiple key metaborates that play pivotal roles in epigenetics regulation. These metabolites include acetyl-CoA, α-ketoglutarate (α-KG), S-adenosyl methionine (SAM), NAD+, and O-linked beta-N-acetylglucosamine (O-GlcNAc), which are the main substrates for DNA methylation and histone post-translation modifications, essential for gene transcriptional regulation and cell fate determination. Tumorigenesis is attributed to many factors, including gene mutations and tumor microenvironment. Mitochondria and epigenetics play essential roles in tumor initiation, evolution, metastasis, and recurrence. Targeting mitochondrial metabolism and epigenetics are promising therapeutic strategies for tumor treatment. In this review, we summarize the roles of mitochondria in key metabolites required for epigenetics modification and in cell fate regulation and discuss the current strategy in cancer therapies via targeting epigenetic modifiers and related enzymes in metabolic regulation. This review is an important contribution to the understanding of the current metabolic-epigenetic-tumorigenesis concept.
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Affiliation(s)
- Yu’e Liu
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Chao Chen
- Department of Neurosurgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
| | - Xinye Wang
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yihong Sun
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jin Zhang
- Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Juxiang Chen
- Department of Neurosurgery, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China
- Correspondence: (J.C.); (Y.S.)
| | - Yufeng Shi
- Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China
- Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai 200092, China
- Correspondence: (J.C.); (Y.S.)
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13
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Fiorentino F, Castiello C, Mai A, Rotili D. Therapeutic Potential and Activity Modulation of the Protein Lysine Deacylase Sirtuin 5. J Med Chem 2022; 65:9580-9606. [PMID: 35802779 PMCID: PMC9340778 DOI: 10.1021/acs.jmedchem.2c00687] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Sirtiun 5 (SIRT5) is a NAD+-dependent protein lysine deacylase primarily located in mitochondria. SIRT5 displays an affinity for negatively charged acyl groups and mainly catalyzes lysine deglutarylation, desuccinylation, and demalonylation while possessing weak deacetylase activity. SIRT5 substrates play crucial roles in metabolism and reactive oxygen species (ROS) detoxification, and SIRT5 activity is protective in neuronal and cardiac physiology. Moreover, SIRT5 exhibits a dichotomous role in cancer, acting as context-dependent tumor promoter or suppressor. Given its multifaceted activity, SIRT5 is a promising target in the design of activators or inhibitors that might act as therapeutics in many pathologies, including cancer, cardiovascular disorders, and neurodegeneration. To date, few cellular-active peptide-based SIRT5 inhibitors (SIRT5i) have been described, and potent and selective small-molecule SIRT5i have yet to be discovered. In this perspective, we provide an outline of SIRT5's roles in different biological settings and describe SIRT5 modulators in terms of their mode of action, pharmacological activity, and structure-activity relationships.
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Affiliation(s)
- Francesco Fiorentino
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzala Aldo Moro 5, Rome 00185, Italy
| | - Carola Castiello
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzala Aldo Moro 5, Rome 00185, Italy
| | - Antonello Mai
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzala Aldo Moro 5, Rome 00185, Italy
- Pasteur
Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, Piazzala Aldo Moro 5, Rome 00185, Italy
| | - Dante Rotili
- Department
of Drug Chemistry and Technologies, Sapienza
University of Rome, Piazzala Aldo Moro 5, Rome 00185, Italy
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14
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Muoio DM, Williams AS, Grimsrud PA. Mitochondrial lysine acylation and cardiometabolic stress: Truth or consequence? CURRENT OPINION IN PHYSIOLOGY 2022; 27:100551. [PMID: 39606008 PMCID: PMC11601992 DOI: 10.1016/j.cophys.2022.100551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Disruptions in oxidative metabolism are often accompanied by tissue accumulation of catabolic carbon intermediates, including acyl CoA molecules that can react with the epsilon amino group of lysine residues on cellular proteins. In general, acyl-lysine post-translational modifications (PTMs) on mitochondrial proteins correlate negatively with energy homeostasis and are offset by the mitochondrial sirtuins, a prominent family of NAD+-dependent deacylases linked favorably to longevity and metabolic resilience. Whereas studies over the past decade elicited widespread conjecture as to the far-reaching regulatory roles of these PTMs, more recent work has stirred controversy in this field of study. This review draws attention to discrepancies in the science, challenges current dogma, and encourages new perspectives on the physiological relevance of mitochondrial lysine acylation.
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Affiliation(s)
- Deborah M. Muoio
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute
- Departments of Medicine, Duke Molecular Physiology Institute
- Pharmacology and Cancer Biology. Duke Molecular Physiology Institute
| | - Ashley S. Williams
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute
| | - Paul A. Grimsrud
- Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute
- Departments of Medicine, Duke Molecular Physiology Institute
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15
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Reiter RJ, Sharma R, Rosales-Corral S, de Campos Zuccari DAP, de Almeida Chuffa LG. Melatonin: A mitochondrial resident with a diverse skill set. Life Sci 2022; 301:120612. [PMID: 35523285 DOI: 10.1016/j.lfs.2022.120612] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/25/2022] [Accepted: 04/30/2022] [Indexed: 12/12/2022]
Abstract
Melatonin is an ancient molecule that originated in bacteria. When these prokaryotes were phagocytized by early eukaryotes, they eventually developed into mitochondria and chloroplasts. These new organelles retained the melatonin synthetic capacity of their forerunners such that all present-day animal and plant cells may produce melatonin in their mitochondria and chloroplasts. Melatonin concentrations are higher in mitochondria than in other subcellular compartments. Isolated mouse oocyte mitochondria form melatonin when they are incubated with serotonin, a necessary precursor. Oocyte mitochondria subsequently give rise to these organelles in all adult vertebrate cells where they continue to synthesize melatonin. The enzymes that convert serotonin to melatonin, i.e., arylalkylamine-N-acetyltransferase (AANAT) and acetylserotonin-O-methyltransferase, have been identified in brain mitochondria which, when incubated with serotonin, also form melatonin. Melatonin is a potent antioxidant and anti-cancer agent and is optimally positioned in mitochondria to aid in the maintenance of oxidative homeostasis and to reduce cancer cell transformation. Melatonin stimulates the transfer of mitochondria from healthy cells to damaged cells via tunneling nanotubes. Melatonin also regulates the major NAD+-dependent deacetylase, sirtuin 3, in the mitochondria. Disruptions of mitochondrial melatonin synthesis may contribute to a number of mitochondria-related diseases, as discussed in this review.
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Affiliation(s)
- Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | - Ramaswamy Sharma
- Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA.
| | - Sergio Rosales-Corral
- Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco CP45150, Mexico
| | | | - Luiz Gustavo de Almeida Chuffa
- Department of Structural and Functional Biology, Institute of Biosciences, UNESP-São Paulo State University, Botucatu, São Paulo 18618-689, Brazil
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16
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Deniz FSŞ, Eren G, Orhan IE. Flavonoids as Sirtuin Modulators. Curr Top Med Chem 2022; 22:790-805. [PMID: 35466876 DOI: 10.2174/1568026622666220422094744] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/03/2022] [Accepted: 03/06/2022] [Indexed: 11/22/2022]
Abstract
Sirtuins (SIRTs) are described as NAD+-dependent deacetylases, also known as class III histone deacetylases. So far, seven sirtuin genes (SIRTS 1-7) have been identified and characterized in mammals and also known to occur in bacteria and eukaryotes. SIRTs are involved in various biological processes including endocrine system, apoptosis, aging and longevity, diabetes, rheumatoid arthritis, obesity, inflammation, etc. Among them, the best characterized one is SIRT1. Actually, small molecules seem to be the most effective SIRT modulators. Flavonoids have been reported to possess many positive effects favrable for human health, while a relatively less research has been reported so far on their funcions as SIRT modulation mechanisms. In this regard, we herein aimed to focus on modulatory effects of flavonoids on SIRTs as the most common secondary metabolites in natural products. Our literature survey covering the years of 2006-2021 pointed out that flavonoids frequently interact with SIRT1 and SIRT3 followed by SIRT6. It can be also concluded that some popular flavonoid derivatives, e.g. resveratrol, quercetin, and catechin derivatives came forward in terms of SIRT modulation.
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Affiliation(s)
| | - Gökçen Eren
- Faculty of Pharmacy, Gazi University, 06330 Ankara
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17
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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: 4] [Impact Index Per Article: 1.3] [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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18
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Ul Haq MF, Kayani MA, Arshad T, Hadi Anwar RA, Saeed N, Shafique R, Abbasi SF, Ahmed MW, Mahjabeen I. Genetic interactions of mitochondrial sirtuins in brain tumorigenesis. Future Oncol 2022; 18:597-611. [PMID: 35034477 DOI: 10.2217/fon-2021-0264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Purpose: The present study was designed to understand the role of expression variations of mitochondrial imported sirtuins in brain tumorigenesis. The expression levels of mitochondrial imported sirtuins were further analyzed for biomarker potential. Methods: Samples from 200 brain tumors and 200 healthy control tissues were used for expression analysis using qPCR and for DNA damage using LORD-Q analysis. Results: Significant deregulation of SIRT3 (p = 0.002), SIRT4 (p = 0.03) and SIRT5 (p = 0.006) was observed in brain tumors versus controls. Co-expression analysis showed a significant correlation between the mitochondrial imported sirtuins versus apoptotic genes. LORD-Q analysis showed a significantly increased frequency of lesions/10 kb of mitochondrial imported sirtuins (p < 0.0001) in brain tumor tissue versus controls. Conclusion: The present study showed a correlation between variations of mitochondrial imported sirtuins and increased brain tumor risk.
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Affiliation(s)
- Maria Fazal Ul Haq
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Mahmood Akhtar Kayani
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Taaha Arshad
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Raja Abdul Hadi Anwar
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Nadia Saeed
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Rabia Shafique
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Sumaira Fidda Abbasi
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Islamabad, Pakistan
| | - Malik Waqar Ahmed
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Islamabad, Pakistan.,Pakistan Institute of Rehabilitation Sciences (PIRS), Isra University Islamabad Campus, Islamabad, Pakistan
| | - Ishrat Mahjabeen
- Cancer Genetics & Epigenetics Research Group, Department of Biosciences, COMSATS University, Islamabad, Pakistan
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19
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Resveratrol Analog 4-Bromo-Resveratrol Inhibits Gastric Cancer Stemness through the SIRT3-c-Jun N-Terminal Kinase Signaling Pathway. Curr Issues Mol Biol 2021; 44:63-72. [PMID: 35723384 PMCID: PMC8929134 DOI: 10.3390/cimb44010005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 12/24/2022] Open
Abstract
Chemotherapy is the treatment of choice for gastric cancer, but the currently available therapeutic drugs have limited efficacy. Studies have suggested that gastric cancer stem cells may play a key role in drug resistance in chemotherapy. Therefore, new agents that selectively target gastric cancer stem cells in gastric tumors are urgently required. Sirtuin-3 (SIRT3) is a deacetylase that regulates mitochondrial metabolic homeostasis to maintain stemness in glioma stem cells. Targeting the mitochondrial protein SIRT3 may provide a novel therapeutic option for gastric cancer treatment. However, the mechanism by which stemness is regulated through SIRT3 inhibition in gastric cancer remains unknown. We evaluated the stemness inhibition ability of the SIRT3 inhibitor 4′-bromo-resveratrol (4-BR), an analog of resveratrol in human gastric cancer cells. Our results suggested that 4-BR inhibited gastric cancer cell stemness through the SIRT3-c-Jun N-terminal kinase pathway and may aid in gastric cancer stem-cell–targeted therapy.
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20
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Chen CL, Lin CY, Kung HJ. Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers. Int J Mol Sci 2021; 22:13435. [PMID: 34948229 PMCID: PMC8708687 DOI: 10.3390/ijms222413435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 12/26/2022] Open
Abstract
Increasing evidence suggests that tumor development requires not only oncogene/tumor suppressor mutations to drive the growth, survival, and metastasis but also metabolic adaptations to meet the increasing energy demand for rapid cellular expansion and to cope with the often nutritional and oxygen-deprived microenvironment. One well-recognized strategy is to shift the metabolic flow from oxidative phosphorylation (OXPHOS) or respiration in mitochondria to glycolysis or fermentation in cytosol, known as Warburg effects. However, not all cancer cells follow this paradigm. In the development of prostate cancer, OXPHOS actually increases as compared to normal prostate tissue. This is because normal prostate epithelial cells divert citrate in mitochondria for the TCA cycle to the cytosol for secretion into seminal fluid. The sustained level of OXPHOS in primary tumors persists in progression to an advanced stage. As such, targeting OXPHOS and mitochondrial activities in general present therapeutic opportunities. In this review, we summarize the recent findings of the key regulators of the OXPHOS pathway in prostate cancer, ranging from transcriptional regulation, metabolic regulation to genetic regulation. Moreover, we provided a comprehensive update of the current status of OXPHOS inhibitors for prostate cancer therapy. A challenge of developing OXPHOS inhibitors is to selectively target cancer mitochondria and spare normal counterparts, which is also discussed.
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Affiliation(s)
- Chia-Lin Chen
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; (C.-L.C.); (C.-Y.L.)
| | - Ching-Yu Lin
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; (C.-L.C.); (C.-Y.L.)
| | - Hsing-Jien Kung
- Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; (C.-L.C.); (C.-Y.L.)
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County 350, Taiwan
- Comprehensive Cancer Center, Department of Biochemistry and Molecular Medicine, University of California at Davis, Sacramento, CA 95817, USA
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21
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Curry AM, White DS, Donu D, Cen Y. Human Sirtuin Regulators: The "Success" Stories. Front Physiol 2021; 12:752117. [PMID: 34744791 PMCID: PMC8568457 DOI: 10.3389/fphys.2021.752117] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/29/2021] [Indexed: 12/15/2022] Open
Abstract
The human sirtuins are a group of NAD+-dependent protein deacylases. They “erase” acyl modifications from lysine residues in various cellular targets including histones, transcription factors, and metabolic enzymes. Through these far-reaching activities, sirtuins regulate a diverse array of biological processes ranging from gene transcription to energy metabolism. Human sirtuins have been intensely pursued by both academia and industry as therapeutic targets for a broad spectrum of diseases such as cancer, neurodegenerative diseases, and metabolic disorders. The last two decades have witnessed a flood of small molecule sirtuin regulators. However, there remain relatively few compounds targeting human sirtuins in clinical development. This reflects the inherent issues concerning the development of isoform-selective and potent molecules with good drug-like properties. In this article, small molecule sirtuin regulators that have advanced into clinical trials will be discussed in details as “successful” examples for future drug development. Special attention is given to the discovery of these compounds, the mechanism of action, pharmacokinetics analysis, formulation, as well as the clinical outcomes observed in the trials.
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Affiliation(s)
- Alyson M Curry
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, United States
| | - Dawanna S White
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, United States
| | - Dickson Donu
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, United States
| | - Yana Cen
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, United States.,Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA, United States
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