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Mantoan Ritter L, Annear NMP, Baple EL, Ben-Chaabane LY, Bodi I, Brosson L, Cadwgan JE, Coslett B, Crosby AH, Davies DM, Daykin N, Dedeurwaerdere S, Dühring Fenger C, Dunlop EA, Elmslie FV, Girodengo M, Hambleton S, Jansen AC, Johnson SR, Kearley KC, Kingswood JC, Laaniste L, Lachlan K, Latchford A, Madsen RR, Mansour S, Mihaylov SR, Muhammed L, Oliver C, Pepper T, Rawlins LE, Schim van der Loeff I, Siddiqui A, Takhar P, Tatton-Brown K, Tee AR, Tibarewal P, Tye C, Ultanir SK, Vanhaesebroeck B, Zare B, Pal DK, Bateman JM. mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node. Orphanet J Rare Dis 2025; 20:256. [PMID: 40426219 PMCID: PMC12107773 DOI: 10.1186/s13023-025-03740-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 04/16/2025] [Indexed: 05/29/2025] Open
Abstract
Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.
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Affiliation(s)
- Laura Mantoan Ritter
- King's College London Institute of Psychiatry Psychology and Neuroscience, London, UK
- King's College Hospital NHS Foundation Trust, London, UK
| | - Nicholas M P Annear
- St George's University Hospitals NHS Foundation Trust, London, UK
- School of Health & Medical Sciences, City St George's, University of London, London, UK
| | | | - Leila Y Ben-Chaabane
- King's College London Institute of Psychiatry Psychology and Neuroscience, London, UK
| | - Istvan Bodi
- King's College Hospital NHS Foundation Trust, London, UK
| | | | | | | | | | | | | | | | | | | | - Frances V Elmslie
- St George's University Hospitals NHS Foundation Trust, London, UK
- School of Health & Medical Sciences, City St George's, University of London, London, UK
| | - Marie Girodengo
- King's College London Institute of Psychiatry Psychology and Neuroscience, London, UK
- The Francis Crick Institute, London, UK
| | - Sophie Hambleton
- Newcastle University Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | | | - Simon R Johnson
- Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre and Biodiscovery Institute, Translational Medical Sciences, University of Nottingham, Nottingham, UK
| | - Kelly C Kearley
- mTOR Node Advisory Panel (MAP), London, UK
- PTEN UK and Ireland Patient Group, London, UK
| | - John C Kingswood
- St George's University Hospitals NHS Foundation Trust, London, UK
| | | | - Katherine Lachlan
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Andrew Latchford
- Polyposis Registry, St Mark's Hospital, London, UK
- Department of Surgery and Cancer, Imperial College London, London, UK
| | | | - Sahar Mansour
- St George's University Hospitals NHS Foundation Trust, London, UK
- School of Health & Medical Sciences, City St George's, University of London, London, UK
| | | | | | | | - Tom Pepper
- PTEN Research, Cheltenham, Gloucestershire, UK
| | | | - Ina Schim van der Loeff
- Newcastle University Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Ata Siddiqui
- King's College Hospital NHS Foundation Trust, London, UK
| | | | - Katrina Tatton-Brown
- St George's University Hospitals NHS Foundation Trust, London, UK
- School of Health & Medical Sciences, City St George's, University of London, London, UK
| | | | | | - Charlotte Tye
- King's College London Institute of Psychiatry Psychology and Neuroscience, London, UK
| | | | | | | | - Deb K Pal
- King's College London Institute of Psychiatry Psychology and Neuroscience, London, UK
| | - Joseph M Bateman
- King's College London Institute of Psychiatry Psychology and Neuroscience, London, UK.
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Saponaro C, Gammaldi N, Cavallo V, Ramírez-Morales MA, Zito FA, Sonnessa M, Vari F, Serra I, De Summa S, Giudetti AM, Trerotola M, Vergara D. Insight into the Regulation of NDRG1 Expression. Int J Mol Sci 2025; 26:3582. [PMID: 40332138 PMCID: PMC12027247 DOI: 10.3390/ijms26083582] [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: 02/02/2025] [Revised: 04/04/2025] [Accepted: 04/09/2025] [Indexed: 05/08/2025] Open
Abstract
The N-Myc Downstream Regulated Gene 1 (NDRG1) protein, a member of a family of four, has emerged as a key regulator of various physiological and pathological processes. Extensive knowledge has been gained on the modulation of NDRG1 expression during endoplasmic reticulum stress, autophagy, and hypoxia. Moreover, new functions have emerged in recent years. Notably, NDRG1 regulates cell differentiation, metabolism, autophagy and vesicular transport. This has raised interest in the molecular mechanisms that control the cellular levels and activity of NDRG1. A series of studies have shown that NDRG1 can be finely regulated at the transcriptional, post-transcriptional, and translational levels. In addition, processes that mediate protein degradation and clearance also play key roles. Furthermore, three different NDRG1 proteoforms with distinct functions have been identified. An important question is the extent to which these proteoforms contribute to the regulation of cellular functions. Given the growing clinical interest in NDRG1, this review provides an overview of the regulatory mechanisms that control NDRG1 abundance, helping to deepen our understanding of the complex mechanisms underlying protein regulation.
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Affiliation(s)
- Concetta Saponaro
- Pathology Department, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy; (C.S.); (F.A.Z.); (M.S.)
| | - Nicola Gammaldi
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (N.G.); (V.C.); (M.A.R.-M.); (F.V.); (I.S.); (A.M.G.)
| | - Viviana Cavallo
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (N.G.); (V.C.); (M.A.R.-M.); (F.V.); (I.S.); (A.M.G.)
| | - Maria Antonieta Ramírez-Morales
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (N.G.); (V.C.); (M.A.R.-M.); (F.V.); (I.S.); (A.M.G.)
| | - Francesco Alfredo Zito
- Pathology Department, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy; (C.S.); (F.A.Z.); (M.S.)
| | - Margherita Sonnessa
- Pathology Department, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy; (C.S.); (F.A.Z.); (M.S.)
| | - Francesco Vari
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (N.G.); (V.C.); (M.A.R.-M.); (F.V.); (I.S.); (A.M.G.)
- Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
| | - Ilaria Serra
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (N.G.); (V.C.); (M.A.R.-M.); (F.V.); (I.S.); (A.M.G.)
- Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
| | - Simona De Summa
- Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori, “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Anna Maria Giudetti
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (N.G.); (V.C.); (M.A.R.-M.); (F.V.); (I.S.); (A.M.G.)
| | - Marco Trerotola
- Laboratory of Cancer Pathology, Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy;
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, 66013 Chieti, Italy
| | - Daniele Vergara
- Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, 73100 Lecce, Italy; (N.G.); (V.C.); (M.A.R.-M.); (F.V.); (I.S.); (A.M.G.)
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Mehta D, Rajput K, Jain D, Bajaj A, Dasgupta U. Unveiling the Role of Mechanistic Target of Rapamycin Kinase (MTOR) Signaling in Cancer Progression and the Emergence of MTOR Inhibitors as Therapeutic Strategies. ACS Pharmacol Transl Sci 2024; 7:3758-3779. [PMID: 39698262 PMCID: PMC11650738 DOI: 10.1021/acsptsci.4c00530] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/08/2024] [Accepted: 11/18/2024] [Indexed: 12/20/2024]
Abstract
The mechanistic target of rapamycin kinase (MTOR) is pivotal for cell growth, metabolism, and survival. It functions through two distinct complexes, mechanistic TORC1 and mechanistic TORC2 (mTORC1 and mTORC2). These complexes function in the development and progression of cancer by regulating different cellular processes, such as protein synthesis, lipid metabolism, and glucose homeostasis. The mTORC1 complex senses nutrients and initiates proliferative signals, and mTORC2 is crucial for cell survival and cytoskeletal rearrangements. mTORC1 and mTORC2 have therefore emerged as potential targets for cancer treatment. Several mTOR inhibitors, including rapamycin and its analogs (rapalogs), primarily target mTORC1 and are effective for specific cancer types. However, these inhibitors often lead to resistance and limited long-term advantages due to the activation of survival pathways through feedback mechanisms. Researchers have created next-generation inhibitors targeting mTORC1 and mTORC2 and dual PI3K/mTOR inhibitors to address these difficulties. These inhibitors demonstrate enhanced anti-tumor effects by simultaneously disrupting multiple signaling pathways and show promise for improved and long-lasting therapies. However, development of resistance and adverse side effects remain a significant obstacle. Recent additions known as RapaLinks have emerged as a boon to counter drug-resistant cancer cells, as they are more potent and provide a more comprehensive blockade of mTOR signaling pathways. This Review combines current research findings and clinical insights to enhance our understanding of the crucial role of mTOR signaling in cancer biology and highlights the evolution of mTOR inhibitors as promising therapeutic approaches.
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Affiliation(s)
- Devashish Mehta
- Amity
Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon-122413, Haryana, India
| | - Kajal Rajput
- Amity
Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon-122413, Haryana, India
| | - Dolly Jain
- Laboratory
of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone Faridabad-Gurgaon
Expressway, Faridabad-121001, Haryana, India
| | - Avinash Bajaj
- Laboratory
of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone Faridabad-Gurgaon
Expressway, Faridabad-121001, Haryana, India
| | - Ujjaini Dasgupta
- Amity
Institute of Integrative Sciences and Health, Amity University Haryana, Panchgaon, Manesar, Gurgaon-122413, Haryana, India
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Xu W, Chen H, Xiao H. mTORC2: A neglected player in aging regulation. J Cell Physiol 2024; 239:e31363. [PMID: 38982866 DOI: 10.1002/jcp.31363] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/21/2024] [Accepted: 06/19/2024] [Indexed: 07/11/2024]
Abstract
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a pivotal role in various biological processes, through integrating external and internal signals, facilitating gene transcription and protein translation, as well as by regulating mitochondria and autophagy functions. mTOR kinase operates within two distinct protein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which engage separate downstream signaling pathways impacting diverse cellular processes. Although mTORC1 has been extensively studied as a pro-proliferative factor and a pro-aging hub if activated aberrantly, mTORC2 received less attention, particularly regarding its implication in aging regulation. However, recent studies brought increasing evidence or clues for us, which implies the associations of mTORC2 with aging, as the genetic elimination of unique subunits of mTORC2, such as RICTOR, has been shown to alleviate aging progression in comparison to mTORC1 inhibition. In this review, we first summarized the basic characteristics of mTORC2, including its protein architecture and signaling network. We then focused on reviewing the molecular signaling regulation of mTORC2 in cellular senescence and organismal aging, and proposed the multifaceted regulatory characteristics under senescent and nonsenescent contexts. Next, we outlined the research progress of mTOR inhibitors in the field of antiaging and discussed future prospects and challenges. It is our pleasure if this review article could provide meaningful information for our readers and call forth more investigations working on this topic.
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Affiliation(s)
- Weitong Xu
- The Lab of Aging Research, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Honghan Chen
- The Lab of Aging Research, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hengyi Xiao
- The Lab of Aging Research, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Šimon M, Mikec Š, Atanur SS, Konc J, Morton NM, Horvat S, Kunej T. Whole genome sequencing of mouse lines divergently selected for fatness (FLI) and leanness (FHI) revealed several genetic variants as candidates for novel obesity genes. Genes Genomics 2024; 46:557-575. [PMID: 38483771 PMCID: PMC11024027 DOI: 10.1007/s13258-024-01507-9] [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: 05/04/2023] [Accepted: 02/25/2024] [Indexed: 04/18/2024]
Abstract
BACKGROUND Analysing genomes of animal model organisms is widely used for understanding the genetic basis of complex traits and diseases, such as obesity, for which only a few mouse models exist, however, without their lean counterparts. OBJECTIVE To analyse genetic differences in the unique mouse models of polygenic obesity (Fat line) and leanness (Lean line) originating from the same base population and established by divergent selection over more than 60 generations. METHODS Genetic variability was analysed using WGS. Variants were identified with GATK and annotated with Ensembl VEP. g.Profiler, WebGestalt, and KEGG were used for GO and pathway enrichment analysis. miRNA seed regions were obtained with miRPathDB 2.0, LncRRIsearch was used to predict targets of identified lncRNAs, and genes influencing adipose tissue amount were searched using the IMPC database. RESULTS WGS analysis revealed 6.3 million SNPs, 1.3 million were new. Thousands of potentially impactful SNPs were identified, including within 24 genes related to adipose tissue amount. SNP density was highest in pseudogenes and regulatory RNAs. The Lean line carries SNP rs248726381 in the seed region of mmu-miR-3086-3p, which may affect fatty acid metabolism. KEGG analysis showed deleterious missense variants in immune response and diabetes genes, with food perception pathways being most enriched. Gene prioritisation considering SNP GERP scores, variant consequences, and allele comparison with other mouse lines identified seven novel obesity candidate genes: 4930441H08Rik, Aff3, Fam237b, Gm36633, Pced1a, Tecrl, and Zfp536. CONCLUSION WGS revealed many genetic differences between the lines that accumulated over the selection period, including variants with potential negative impacts on gene function. Given the increasing availability of mouse strains and genetic polymorphism catalogues, the study is a valuable resource for researchers to study obesity.
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Affiliation(s)
- Martin Šimon
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia.
| | - Špela Mikec
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia
| | - Santosh S Atanur
- Faculty of Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, SW7 2AZ, UK
- Centre for Genomic and Experimental Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Janez Konc
- Laboratory for Molecular Modeling, National Institute of Chemistry, Ljubljana, 1000, Slovenia
| | - Nicholas M Morton
- The Queen's Medical Research Institute, Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Simon Horvat
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia
| | - Tanja Kunej
- Chair of Genetics, Animal Biotechnology and Immunology, Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Domžale, 1230, Slovenia.
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Jhanwar-Uniyal M, Zeller SL, Spirollari E, Das M, Hanft SJ, Gandhi CD. Discrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets. Cells 2024; 13:409. [PMID: 38474373 PMCID: PMC10930964 DOI: 10.3390/cells13050409] [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: 01/16/2024] [Revised: 02/14/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions via its discrete binding partners to form two multiprotein complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin-sensitive mTORC1, which regulates protein synthesis and cell growth, is tightly controlled by PI3K/Akt and is nutrient-/growth factor-sensitive. In the brain, mTORC1 is also sensitive to neurotransmitter signaling. mTORC2, which is modulated by growth factor signaling, is associated with ribosomes and is insensitive to rapamycin. mTOR regulates stem cell and cancer stem cell characteristics. Aberrant Akt/mTOR activation is involved in multistep tumorigenesis in a variety of cancers, thereby suggesting that the inhibition of mTOR may have therapeutic potential. Rapamycin and its analogues, known as rapalogues, suppress mTOR activity through an allosteric mechanism that only suppresses mTORC1, albeit incompletely. ATP-catalytic binding site inhibitors are designed to inhibit both complexes. This review describes the regulation of mTOR and the targeting of its complexes in the treatment of cancers, such as glioblastoma, and their stem cells.
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Affiliation(s)
- Meena Jhanwar-Uniyal
- Department of Neurosurgery, Westchester Medical Center, New York Medical College, Valhalla, NY 10595, USA
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Ragupathi A, Kim C, Jacinto E. The mTORC2 signaling network: targets and cross-talks. Biochem J 2024; 481:45-91. [PMID: 38270460 PMCID: PMC10903481 DOI: 10.1042/bcj20220325] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/29/2023] [Accepted: 12/18/2023] [Indexed: 01/26/2024]
Abstract
The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.
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Affiliation(s)
- Aparna Ragupathi
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, U.S.A
| | - Christian Kim
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, U.S.A
| | - Estela Jacinto
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, U.S.A
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Panwar V, Singh A, Bhatt M, Tonk RK, Azizov S, Raza AS, Sengupta S, Kumar D, Garg M. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct Target Ther 2023; 8:375. [PMID: 37779156 PMCID: PMC10543444 DOI: 10.1038/s41392-023-01608-z] [Citation(s) in RCA: 299] [Impact Index Per Article: 149.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/25/2023] [Accepted: 08/14/2023] [Indexed: 10/03/2023] Open
Abstract
The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain cellular homeostasis. The mTOR signaling cascade consists of two distinct multi-subunit complexes named mTOR complex 1/2 (mTORC1/2). mTOR catalyzes the phosphorylation of several critical proteins like AKT, protein kinase C, insulin growth factor receptor (IGF-1R), 4E binding protein 1 (4E-BP1), ribosomal protein S6 kinase (S6K), transcription factor EB (TFEB), sterol-responsive element-binding proteins (SREBPs), Lipin-1, and Unc-51-like autophagy-activating kinases. mTOR signaling plays a central role in regulating translation, lipid synthesis, nucleotide synthesis, biogenesis of lysosomes, nutrient sensing, and growth factor signaling. The emerging pieces of evidence have revealed that the constitutive activation of the mTOR pathway due to mutations/amplification/deletion in either mTOR and its complexes (mTORC1 and mTORC2) or upstream targets is responsible for aging, neurological diseases, and human malignancies. Here, we provide the detailed structure of mTOR, its complexes, and the comprehensive role of upstream regulators, as well as downstream effectors of mTOR signaling cascades in the metabolism, biogenesis of biomolecules, immune responses, and autophagy. Additionally, we summarize the potential of long noncoding RNAs (lncRNAs) as an important modulator of mTOR signaling. Importantly, we have highlighted the potential of mTOR signaling in aging, neurological disorders, human cancers, cancer stem cells, and drug resistance. Here, we discuss the developments for the therapeutic targeting of mTOR signaling with improved anticancer efficacy for the benefit of cancer patients in clinics.
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Affiliation(s)
- Vivek Panwar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173229, India
| | - Aishwarya Singh
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida, Uttar Pradesh, 201313, India
| | - Manini Bhatt
- Department of Biomedical Engineering, Indian Institute of Technology, Ropar, Punjab, 140001, India
| | - Rajiv K Tonk
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University (DPSRU), New Delhi, 110017, India
| | - Shavkatjon Azizov
- Laboratory of Biological Active Macromolecular Systems, Institute of Bioorganic Chemistry, Academy of Sciences Uzbekistan, Tashkent, 100125, Uzbekistan
- Faculty of Life Sciences, Pharmaceutical Technical University, 100084, Tashkent, Uzbekistan
| | - Agha Saquib Raza
- Rajive Gandhi Super Speciality Hospital, Tahirpur, New Delhi, 110093, India
| | - Shinjinee Sengupta
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida, Uttar Pradesh, 201313, India.
| | - Deepak Kumar
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Shoolini University, Solan, Himachal Pradesh, 173229, India.
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida, Uttar Pradesh, 201313, India.
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Maiese K. Cognitive Impairment in Multiple Sclerosis. Bioengineering (Basel) 2023; 10:871. [PMID: 37508898 PMCID: PMC10376413 DOI: 10.3390/bioengineering10070871] [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: 06/20/2023] [Revised: 07/19/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
Almost three million individuals suffer from multiple sclerosis (MS) throughout the world, a demyelinating disease in the nervous system with increased prevalence over the last five decades, and is now being recognized as one significant etiology of cognitive loss and dementia. Presently, disease modifying therapies can limit the rate of relapse and potentially reduce brain volume loss in patients with MS, but unfortunately cannot prevent disease progression or the onset of cognitive disability. Innovative strategies are therefore required to address areas of inflammation, immune cell activation, and cell survival that involve novel pathways of programmed cell death, mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and associated pathways with the apolipoprotein E (APOE-ε4) gene and severe acute respiratory syndrome coronavirus (SARS-CoV-2). These pathways are intertwined at multiple levels and can involve metabolic oversight with cellular metabolism dependent upon nicotinamide adenine dinucleotide (NAD+). Insight into the mechanisms of these pathways can provide new avenues of discovery for the therapeutic treatment of dementia and loss in cognition that occurs during MS.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY 10022, USA
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10
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Gao Y, Tian T. mTOR Signaling Pathway and Gut Microbiota in Various Disorders: Mechanisms and Potential Drugs in Pharmacotherapy. Int J Mol Sci 2023; 24:11811. [PMID: 37511569 PMCID: PMC10380532 DOI: 10.3390/ijms241411811] [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: 06/12/2023] [Revised: 07/15/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
The mammalian or mechanistic target of rapamycin (mTOR) integrates multiple intracellular and extracellular upstream signals involved in the regulation of anabolic and catabolic processes in cells and plays a key regulatory role in cell growth and metabolism. The activation of the mTOR signaling pathway has been reported to be associated with a wide range of human diseases. A growing number of in vivo and in vitro studies have demonstrated that gut microbes and their complex metabolites can regulate host metabolic and immune responses through the mTOR pathway and result in disorders of host physiological functions. In this review, we summarize the regulatory mechanisms of gut microbes and mTOR in different diseases and discuss the crosstalk between gut microbes and their metabolites and mTOR in disorders in the gastrointestinal tract, liver, heart, and other organs. We also discuss the promising application of multiple potential drugs that can adjust the gut microbiota and mTOR signaling pathways. Despite the limited findings between gut microbes and mTOR, elucidating their relationship may provide new clues for the prevention and treatment of various diseases.
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Affiliation(s)
- Yuan Gao
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
| | - Tian Tian
- College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
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11
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Maiese K. Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System. Biomolecules 2023; 13:816. [PMID: 37238686 PMCID: PMC10216724 DOI: 10.3390/biom13050816] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/05/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer's disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY 10022, USA
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12
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Gao J, Yao M, Chang D, Liu J. mTOR (Mammalian Target of Rapamycin): Hitting the Bull's Eye for Enhancing Neurogenesis After Cerebral Ischemia? Stroke 2023; 54:279-285. [PMID: 36321454 DOI: 10.1161/strokeaha.122.040376] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Ischemic stroke remains a leading cause of morbidity and disability around the world. The sequelae of serious neurological damage are irreversible due to body's own limited repair capacity. However, endogenous neurogenesis induced by cerebral ischemia plays a critical role in the repair and regeneration of impaired neural cells after ischemic brain injury. mTOR (mammalian target of rapamycin) kinase has been suggested to regulate neural stem cells ability to self-renew and differentiate into proliferative daughter cells, thus leading to improved cell growth, proliferation, and survival. In this review, we summarized the current evidence to support that mTOR signaling pathways may enhance neurogenesis, angiogenesis, and synaptic plasticity following cerebral ischemia, which could highlight the potential of mTOR to be a viable therapeutic target for the treatment of ischemic brain injury.
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Affiliation(s)
- Jiale Gao
- Beijing Key Laboratory of Pharmacology of Chinese Materia Medica, Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, China (J.G., M.Y., J.L.)
| | - Mingjiang Yao
- Beijing Key Laboratory of Pharmacology of Chinese Materia Medica, Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, China (J.G., M.Y., J.L.)
| | - Dennis Chang
- NICM Health Research Institute, Western Sydney University, Penrith, Australia (D.C.)
| | - Jianxun Liu
- Beijing Key Laboratory of Pharmacology of Chinese Materia Medica, Institute of Basic Medical Sciences of Xiyuan Hospital, China Academy of Chinese Medical Sciences, China (J.G., M.Y., J.L.)
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13
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Cao Y, Han S, Lu H, Luo Y, Guo T, Wu Q, Luo F. Targeting mTOR Signaling by Dietary Polyphenols in Obesity Prevention. Nutrients 2022; 14:nu14235171. [PMID: 36501200 PMCID: PMC9735788 DOI: 10.3390/nu14235171] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/29/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Dietary polyphenols can be utilized to treat obesity and chronic disorders linked to it. Dietary polyphenols can inhibit pre-adipocyte proliferation, adipocyte differentiation, and triglyceride accumulation; meanwhile, polyphenols can also stimulate lipolysis and fatty acid β-oxidation, but the molecular mechanisms of anti-obesity are still unclear. The mechanistic target of rapamycin (mTOR) is a protein kinase that regulates cell growth, survival, metabolism, and immunity. mTOR signaling is also thought to play a key role in the development of metabolic diseases such as obesity. Recent studies showed that dietary polyphenols could target mTOR to reduce obesity. In this review, we systematically summarized the research progress of polyphenols in preventing obesity through the mTOR signaling pathway. Mechanistically, polyphenols can target multiple signaling pathways and gut microbiota to regulate the mTOR signaling pathway to exert anti-obesity effects. The main mechanisms include: modulating lipid metabolism, adipogenesis, inflammation, etc. Dietary polyphenols exerting an anti-obesity effect by targeting mTOR signaling will broaden our understanding of the anti-obesity mechanisms of polyphenols and provide valuable insights for researchers in this novel field.
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Affiliation(s)
- Yunyun Cao
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, Hunan Provincial Key Laboratory of Processed Food for Special Medical Purpose, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Shuai Han
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, Hunan Provincial Key Laboratory of Processed Food for Special Medical Purpose, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Han Lu
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, Hunan Provincial Key Laboratory of Processed Food for Special Medical Purpose, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Yi Luo
- Department of Clinic Medicine, Xiangya School of Medicine, Central South University, Changsha 410008, China
| | - Tianyi Guo
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, Hunan Provincial Key Laboratory of Processed Food for Special Medical Purpose, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Qi Wu
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, Hunan Provincial Key Laboratory of Processed Food for Special Medical Purpose, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Feijun Luo
- Hunan Provincial Key Laboratory of Grain-Oil Deep Process and Quality Control, Hunan Provincial Key Laboratory of Forestry Edible Resources Safety and Processing, Hunan Provincial Key Laboratory of Processed Food for Special Medical Purpose, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
- Correspondence:
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14
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Long noncoding RNA-mediated activation of PROTOR1/PRR5-AKT signaling shunt downstream of PI3K in triple-negative breast cancer. Proc Natl Acad Sci U S A 2022; 119:e2203180119. [PMID: 36269860 PMCID: PMC9618063 DOI: 10.1073/pnas.2203180119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The phosphoinositide 3-kinase (PI3K) pathway represents the most hyperactivated oncogenic pathway in triple-negative breast cancer (TNBC), a highly aggressive tumor subtype encompassing ∼15% of breast cancers and which possesses no targeted therapeutics. Despite critical contributions of its signaling arms to disease pathogenesis, PI3K pathway inhibitors have not achieved expected clinical responses in TNBC, owing largely to a still-incomplete understanding of the compensatory cascades that operate downstream of PI3K. Here, we investigated the contributions of long noncoding RNAs (lncRNAs) to PI3K activities in clinical and experimental TNBC and discovered a prominent role for LINC01133 as a PI3K-AKT signaling effector. We found that LINC01133 exerted protumorigenic roles in TNBC and that it governed a previously undescribed mTOR Complex 2 (mTORC2)-dependent pathway that activated AKT in a PI3K-independent manner. Mechanistically, LINC01133 induced the expression of the mTORC2 component PROTOR1/PRR5 by competitively coupling away its negative messenger RNA (mRNA) regulator, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1). PROTOR1/PRR5 in turn was sufficient and necessary for LINC01133-triggered functions, casting previously unappreciated roles for this Rictor-binding protein in cellular signaling and growth. Notably, LINC01133 antagonism undermined cellular growth, and we show that the LINC01133-PROTOR1/PRR5 pathway was tightly associated with TNBC poor patient survival. Altogether, our findings uncovered a lncRNA-driven signaling shunt that acts as a critical determinant of malignancy downstream of the PI3K pathway and as a potential RNA therapeutic target in clinical TNBC management.
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15
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Abou Daher A, Alkhansa S, Azar WS, Rafeh R, Ghadieh HE, Eid AA. Translational Aspects of the Mammalian Target of Rapamycin Complexes in Diabetic Nephropathy. Antioxid Redox Signal 2022; 37:802-819. [PMID: 34544257 DOI: 10.1089/ars.2021.0217] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Significance: Despite the many efforts put into understanding diabetic nephropathy (DN), direct treatments for DN have yet to be discovered. Understanding the mechanisms behind DN is an essential step in the development of novel therapeutic regimens. The mammalian target of rapamycin (mTOR) pathway has emerged as an important candidate in the quest for drug discovery because of its role in regulating growth, proliferation, as well as protein and lipid metabolism. Recent Advances: Kidney cells have been found to rely on basal autophagy for survival and for conserving kidney integrity. Recent studies have shown that diabetes induces renal autophagy deregulation, leading to kidney injury. Hyper-activation of the mTOR pathway and oxidative stress have been suggested to play a role in diabetes-induced autophagy imbalance. Critical Issues: A detailed understanding of the role of mTOR signaling in diabetes-associated complications is of major importance in the search for a cure. In this review, we provide evidence that mTOR is heavily implicated in diabetes-induced kidney injury. We suggest possible mechanisms through which mTOR exerts its negative effects by increasing insulin resistance, upregulating oxidative stress, and inhibiting autophagy. Future Directions: Both increased oxidative stress and autophagy deregulation are deeply embedded in DN. However, the mechanisms controlling oxidative stress and autophagy are not well understood. Although Akt/mTOR signaling seems to play an important role in oxidative stress and autophagy, further investigation is required to uncover the details of this signaling pathway. Antioxid. Redox Signal. 37, 802-819.
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Affiliation(s)
- Alaa Abou Daher
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Sahar Alkhansa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - William S Azar
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,Department of Physiology and Biophysics, Georgetown University Medical School, Washington, District of Columbia, USA
| | - Rim Rafeh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Hilda E Ghadieh
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.,AUB Diabetes, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
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16
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Thorner J. TOR complex 2 is a master regulator of plasma membrane homeostasis. Biochem J 2022; 479:1917-1940. [PMID: 36149412 PMCID: PMC9555796 DOI: 10.1042/bcj20220388] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/30/2022] [Accepted: 09/01/2022] [Indexed: 11/17/2022]
Abstract
As first demonstrated in budding yeast (Saccharomyces cerevisiae), all eukaryotic cells contain two, distinct multi-component protein kinase complexes that each harbor the TOR (Target Of Rapamycin) polypeptide as the catalytic subunit. These ensembles, dubbed TORC1 and TORC2, function as universal, centrally important sensors, integrators, and controllers of eukaryotic cell growth and homeostasis. TORC1, activated on the cytosolic surface of the lysosome (or, in yeast, on the cytosolic surface of the vacuole), has emerged as a primary nutrient sensor that promotes cellular biosynthesis and suppresses autophagy. TORC2, located primarily at the plasma membrane, plays a major role in maintaining the proper levels and bilayer distribution of all plasma membrane components (sphingolipids, glycerophospholipids, sterols, and integral membrane proteins). This article surveys what we have learned about signaling via the TORC2 complex, largely through studies conducted in S. cerevisiae. In this yeast, conditions that challenge plasma membrane integrity can, depending on the nature of the stress, stimulate or inhibit TORC2, resulting in, respectively, up-regulation or down-regulation of the phosphorylation and thus the activity of its essential downstream effector the AGC family protein kinase Ypk1. Through the ensuing effect on the efficiency with which Ypk1 phosphorylates multiple substrates that control diverse processes, membrane homeostasis is maintained. Thus, the major focus here is on TORC2, Ypk1, and the multifarious targets of Ypk1 and how the functions of these substrates are regulated by their Ypk1-mediated phosphorylation, with emphasis on recent advances in our understanding of these processes.
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Affiliation(s)
- Jeremy Thorner
- Division of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3202, U.S.A
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17
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Mao B, Zhang Q, Ma L, Zhao DS, Zhao P, Yan P. Overview of Research into mTOR Inhibitors. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27165295. [PMID: 36014530 PMCID: PMC9413691 DOI: 10.3390/molecules27165295] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 12/04/2022]
Abstract
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family. The kinase exists in the forms of two complexes, mTORC1 and mTORC2, and it participates in cell growth, proliferation, metabolism, and survival. The kinase activity is closely related to the occurrence and development of multiple human diseases. Inhibitors of mTOR block critical pathways to produce antiviral, anti-inflammatory, antiproliferative and other effects, and they have been applied to research in cancer, inflammation, central nervous system diseases and viral infections. Existing mTOR inhibitors are commonly divided into mTOR allosteric inhibitors, ATP-competitive inhibitors and dual binding site inhibitors, according to their sites of action. In addition, there exist several dual-target mTOR inhibitors that target PI3K, histone deacetylases (HDAC) or ataxia telangiectasia mutated and Rad-3 related (ATR) kinases. This review focuses on the structure of mTOR protein and related signaling pathways as well as the structure and characteristics of various mTOR inhibitors. Non-rapalog allosteric inhibitors will open new directions for the development of new therapeutics specifically targeting mTORC1. The applications of ATP-competitive inhibitors in central nervous system diseases, viral infections and inflammation have laid the foundation for expanding the indications of mTOR inhibitors. Both dual-binding site inhibitors and dual-target inhibitors are beneficial in overcoming mTOR inhibitor resistance.
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Affiliation(s)
- Beibei Mao
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Correspondence: (B.M.); (P.Z.); (P.Y.)
| | - Qi Zhang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Li Ma
- Shandong Provincial Key Laboratory of Molecular Engineering, State Key Laboratory of Biobased Material and Green Papermaking, School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250353, China
| | - Dong-Sheng Zhao
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Pan Zhao
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Correspondence: (B.M.); (P.Z.); (P.Y.)
| | - Peizheng Yan
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
- Correspondence: (B.M.); (P.Z.); (P.Y.)
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18
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A Comprehensive View on the Quercetin Impact on Colorectal Cancer. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27061873. [PMID: 35335239 PMCID: PMC8953922 DOI: 10.3390/molecules27061873] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 03/08/2022] [Accepted: 03/11/2022] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) represents the third type of cancer in incidence and second in mortality worldwide, with the newly diagnosed case number on the rise. Among the diagnosed patients, approximately 70% have no hereditary germ-line mutations or family history of pathology, thus being termed sporadic CRC. Diet and environmental factors are to date considered solely responsible for the development of sporadic CRC; therefore; attention should be directed towards the discovery of preventative actions to combat the CRC initiation, promotion, and progression. Quercetin is a polyphenolic flavonoid plant secondary metabolite with a well-characterized antioxidant activity. It has been extensively reported as an anti-carcinogenic agent in the scientific literature, and the modulated targets of quercetin have been also characterized in the context of CRC, mainly in original research publications. In this fairly comprehensive review, we summarize the molecular targets of quercetin reported to date in in vivo and in vitro CRC models, while also giving background information about the signal transduction pathways that it up- and downregulates. Among the most relevant modulated pathways, the Wnt/β-catenin, PI3K/AKT, MAPK/Erk, JNK, or p38, p53, and NF-κB have been described. With this work, we hope to encourage further quests in the elucidation of quercetin anti-carcinogenic activity as single agent, as dietary component, or as pharmaconutrient delivered in the form of plant extracts.
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19
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Shams R, Ito Y, Miyatake H. Mapping of mTOR drug targets: Featured platforms for anti-cancer drug discovery. Pharmacol Ther 2021; 232:108012. [PMID: 34624427 DOI: 10.1016/j.pharmthera.2021.108012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/25/2021] [Accepted: 09/28/2021] [Indexed: 12/12/2022]
Abstract
The mammalian/mechanistic target of rapamycin (mTOR) is a regulatory protein kinase involved in cell growth and proliferation. mTOR is usually assembled in two different complexes with different regulatory mechanisms, mTOR complex 1 (mTORC1) and mTORC2, which are involved in different functions such as cell proliferation and cytoskeleton assembly, respectively. In cancer cells, mTOR is hyperactivated in response to metabolic alterations and/or oncogenic signals to overcome the stressful microenvironments. Therefore, recent research progress for mTOR inhibition involves a variety of compounds that have been developed to disturb the metabolic processes of cancer cells through mTOR inhibition. In addition to competitive or allosteric inhibition, a new inhibition strategy that emerged mTOR complexes destabilization has recently been a concern. Here, we review the history of mTOR and its inhibition, along with the timeline of the mTOR inhibitors. We also introduce prospective drug targets to inhibit mTOR by disrupting the complexation of the components with peptides and small molecules.
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Affiliation(s)
- Raef Shams
- Emergent Bioengineering Materials Research Team, RIKEN Center for Emergent Matter Science, RIKEN, Wako, Saitama 351-0198, Japan; Department of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan.
| | - Yoshihiro Ito
- Emergent Bioengineering Materials Research Team, RIKEN Center for Emergent Matter Science, RIKEN, Wako, Saitama 351-0198, Japan; Nano Medical Engineering Laboratory, RIKEN Cluster for Pioneering Research, RIKEN, Wako, Saitama 351-0198, Japan
| | - Hideyuki Miyatake
- Department of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan; Nano Medical Engineering Laboratory, RIKEN Cluster for Pioneering Research, RIKEN, Wako, Saitama 351-0198, Japan.
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20
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Abstract
The ageing population is becoming a significant socio-economic issue. To address the expanding health gap, it is important to deepen our understanding of the mechanisms underlying ageing in various organisms at the single-cell level. The discovery of the antifungal, immunosuppressive, and anticancer drug rapamycin, which possesses the ability to extend the lifespan of several species, has prompted extensive research in the areas of cell metabolic regulation, development, and senescence. At the centre of this research is the mTOR pathway, with key roles in cell growth, proteosynthesis, ribosomal biogenesis, transcriptional regulation, glucose and lipid metabolism, and autophagy. Recently, it has become obvious that mTOR dysregulation is involved in several age-related diseases, such as cancer, neurodegenerative diseases, and type 2 diabetes mellitus. Additionally, mTOR hyperactivation affects the process of ageing per se. In this review, we provide an overview of recent insights into the mTOR signalling pathway, including its regulation and its influence on various hallmarks of ageing at the cellular level.
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Affiliation(s)
- Zofia Chrienova
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czechia
| | - Eugenie Nepovimova
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czechia
| | - Kamil Kuca
- Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove, Czechia
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21
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Liu B, Li N, He Z, Zhang X, Duan G. Emerging Role of Serum Glucocorticoid-Regulated Kinase 1 in Pathological Pain. Front Mol Neurosci 2021; 14:683527. [PMID: 34093127 PMCID: PMC8177009 DOI: 10.3389/fnmol.2021.683527] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Accepted: 04/22/2021] [Indexed: 11/28/2022] Open
Abstract
Currently, the management of acute and chronic pain in clinical practice remains unsatisfactory due to the existence of limited effective treatments, and novel therapeutic strategies for pathological pain are urgently needed. In the past few decades, the role of serum and glucocorticoid-inducible kinase 1 (SGK1) in the development of pain and diurnal rhythms has been implicated in numerous studies. The expression levels of SGK1 mRNA and protein were found to be elevated in the spinal cord and brain in various pathological pain models. Blocking SGK1 significantly attenuated pain-like responses and the development of pathological pain. These studies provide strong evidence that SGK1 plays a role in the development of various types of pathological pain and that targeting SGK1 may be a novel therapeutic strategy for pain management. In this review article, we provide evidence from animal models for the potential role of SGK1 in the regulation of pathological pain caused by inflammation, nerve injury, psychiatric disorders, and chronic opioid exposure.
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Affiliation(s)
- Baowen Liu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ningbo Li
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhigang He
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xianwei Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guangyou Duan
- Department of Anesthesiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
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22
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Lv Z, Yue Z, Shao Y, Li C, Zhao X, Guo M. mTORC2/Rictor is essential for coelomocyte endocytosis in Apostichopus japonicus. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 118:104000. [PMID: 33444645 DOI: 10.1016/j.dci.2021.104000] [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: 11/15/2020] [Revised: 01/06/2021] [Accepted: 01/07/2021] [Indexed: 06/12/2023]
Abstract
Endocytosis plays an important role in the immune defence systems of invertebrates through the interaction between the mechanical target of rapamycin complex 2 (mTORC2) and the AGC kinase family. Rictor is the most important unique subunit protein of mTORC2 and is thought to regulate almost all functions of mTORC2, including endocytosis. In the present study, a novel invertebrate Rictor homologue was identified from Apostichopus japonicus (designated as AjRictor) via the rapid amplification of cDNA ends (RACE). Spatial expression analysis indicated that AjRictor is ubiquitously expressed in all the examined tissues and has the highest transcript level in coelomocytes. Vibrio splendidus challenge in vivo and lipopolysaccharide (LPS) exposure in vitro could remarkably up-regulate the messenger RNA (mRNA) expression of AjRictor compared with the control group. AjRictor knockdown by 0.49- and 0.69-fold resulted in the significant decrease in endocytosis rate by 0.53- (P < 0.01) and 0.59-fold (P < 0.01) in vivo and in vitro compared with the control group, respectively. Similarly, the treatment of coelomocytes with rapamycin for 24 h and the destruction of the assembly of mTORC2 markedly decreased the endocytosis rate of the coelomocytes by 35.92% (P < 0.05). We detected the expression levels of endocytosis-related molecular markers after AjRictor knockdown and rapamycin treatment to further study the molecular mechanism between mTORC2 and endocytosis. Our results showed that AGC kinase family members (PKCα and Pan1) and the phosphorylation level of AktS473 were remarkably decreased after reducing mTORC2 activity; thus, mTORC2/Rictor plays a key role in the immune regulation of endocytosis in coelomocytes. Our current study indicates that mTORC2/Rictor is involved in the coelomocyte endocytosis of sea cucumber and plays an essential regulation role in defending pathogen invasion.
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Affiliation(s)
- Zhimeng Lv
- School of Marine Sciences, Ningbo University, Ningbo, 315211, PR China
| | - Zongxu Yue
- School of Marine Sciences, Ningbo University, Ningbo, 315211, PR China
| | - Yina Shao
- School of Marine Sciences, Ningbo University, Ningbo, 315211, PR China.
| | - Chenghua Li
- School of Marine Sciences, Ningbo University, Ningbo, 315211, PR China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, PR China.
| | - Xuelin Zhao
- School of Marine Sciences, Ningbo University, Ningbo, 315211, PR China
| | - Ming Guo
- School of Marine Sciences, Ningbo University, Ningbo, 315211, PR China
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Baffi TR, Lordén G, Wozniak JM, Feichtner A, Yeung W, Kornev AP, King CC, Del Rio JC, Limaye AJ, Bogomolovas J, Gould CM, Chen J, Kennedy EJ, Kannan N, Gonzalez DJ, Stefan E, Taylor SS, Newton AC. mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif. Sci Signal 2021; 14:eabe4509. [PMID: 33850054 PMCID: PMC8208635 DOI: 10.1126/scisignal.abe4509] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The complex mTORC2 is accepted to be the kinase that controls the phosphorylation of the hydrophobic motif, a key regulatory switch for AGC kinases, although whether mTOR directly phosphorylates this motif remains controversial. Here, we identified an mTOR-mediated phosphorylation site that we termed the TOR interaction motif (TIM; F-x3-F-pT), which controls the phosphorylation of the hydrophobic motif of PKC and Akt and the activity of these kinases. The TIM is invariant in mTORC2-dependent AGC kinases, is evolutionarily conserved, and coevolved with mTORC2 components. Mutation of this motif in Akt1 and PKCβII abolished cellular kinase activity by impairing activation loop and hydrophobic motif phosphorylation. mTORC2 directly phosphorylated the PKC TIM in vitro, and this phosphorylation event was detected in mouse brain. Overexpression of PDK1 in mTORC2-deficient cells rescued hydrophobic motif phosphorylation of PKC and Akt by a mechanism dependent on their intrinsic catalytic activity, revealing that mTORC2 facilitates the PDK1 phosphorylation step, which, in turn, enables autophosphorylation. Structural analysis revealed that PKC homodimerization is driven by a TIM-containing helix, and biophysical proximity assays showed that newly synthesized, unphosphorylated PKC dimerizes in cells. Furthermore, disruption of the dimer interface by stapled peptides promoted hydrophobic motif phosphorylation. Our data support a model in which mTORC2 relieves nascent PKC dimerization through TIM phosphorylation, recruiting PDK1 to phosphorylate the activation loop and triggering intramolecular hydrophobic motif autophosphorylation. Identification of TIM phosphorylation and its role in the regulation of PKC provides the basis for AGC kinase regulation by mTORC2.
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Affiliation(s)
- Timothy R Baffi
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
- Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA
| | - Gema Lordén
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
| | - Jacob M Wozniak
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
- Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA
| | - Andreas Feichtner
- Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, Innsbruck A-6020, Austria
| | - Wayland Yeung
- Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
| | - Alexandr P Kornev
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
| | - Charles C King
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
| | - Jason C Del Rio
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
- Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA
| | - Ameya J Limaye
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
| | - Julius Bogomolovas
- Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA
| | - Christine M Gould
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
- Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA
| | - Ju Chen
- Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA
| | - Eileen J Kennedy
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
| | - Natarajan Kannan
- Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
| | - David J Gonzalez
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA
| | - Eduard Stefan
- Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck, Innsbruck A-6020, Austria
| | - Susan S Taylor
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
- Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA
| | - Alexandra C Newton
- Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
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Popova NV, Jücker M. The Role of mTOR Signaling as a Therapeutic Target in Cancer. Int J Mol Sci 2021; 22:ijms22041743. [PMID: 33572326 PMCID: PMC7916160 DOI: 10.3390/ijms22041743] [Citation(s) in RCA: 171] [Impact Index Per Article: 42.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/30/2021] [Accepted: 02/03/2021] [Indexed: 12/11/2022] Open
Abstract
The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.
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Affiliation(s)
- Nadezhda V. Popova
- Laboratory of Receptor Cell Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Str., 16/10, 117997 Moscow, Russia;
| | - Manfred Jücker
- Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany
- Correspondence: ; Tel.: +49-(0)-40-7410-56339
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25
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Chawsheen MA, Dash PR. mTOR modulates resistance to gemcitabine in lung cancer in an MTORC2 dependent mechanism. Cell Signal 2021; 81:109934. [PMID: 33545231 DOI: 10.1016/j.cellsig.2021.109934] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 01/28/2021] [Accepted: 01/28/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND Lung cancer has a poor prognosis partly due to a lack of response to treatments such as the chemotherapy drug gemcitabine. Combinations of chemotherapy drugs with signal transduction inhibitors may be more effective treatments. In this study we have investigated the impact of targeting the mTOR signalling pathway on the efficacy of gemcitabine in different cancer cell lines. METHODS Time-lapse microscopy, immuno-staining, and western blot techniques were used to evaluate the efficacy of applied treatments either in measuring phosphorylation levels of mTOR down-stream targets or in tracking down the fate of targeted cells. Reactive oxygen species and relative levels of protein phosphorylation were also quantified. For comparison between treated groups t-test and analysis of variance test were applied. RESULTS Our data showed that mTORC1 has no role in sensitising A549 lung cancer cells to gemcitabine. However, targeting mTORC1/2 with the pharmacological inhibitor torin1 or by over-expressing Deptor, the negative regulator of mTOR signalling, sensitised these cells to gemcitabine. Silencing mTORC2, but not mTORC1, induced apoptosis and significantly improved the apoptosis-inducing effects of gemcitabine. Results also suggest that Rictor is required to maintain cell survival through modulating p38α, ERK1/2, RSK1/2/3 and the transcription factor STAT3. Multiple cell line comparisons revealed that PANC-1 pancreatic cancer cells were also sensitive to mTOR inhibition, but MCF7 breast cancer, MCF10A breast epithelial and H727 lung cancer cell lines were more resistant to the treatment. CONCLUSIONS Inhibition of mTORC2 may have benefits in the treatment of gemcitabine resistant cancers, and the genetic background of the cell line may determine its response to mTOR inhibition.
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Affiliation(s)
| | - Philip R Dash
- University of Reading, School of Biological Sciences, Reading, UK
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26
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Sang Y, Kong P, Zhang S, Zhang L, Cao Y, Duan X, Sun T, Tao Z, Liu W. SGK1 in Human Cancer: Emerging Roles and Mechanisms. Front Oncol 2021; 10:608722. [PMID: 33542904 PMCID: PMC7851074 DOI: 10.3389/fonc.2020.608722] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022] Open
Abstract
Serum and glucocorticoid-induced protein kinase 1 (SGK1) is a member of the "AGC" subfamily of protein kinases, which shares structural and functional similarities with the AKT family of kinases and displays serine/threonine kinase activity. Aberrant expression of SGK1 has profound cellular consequences and is closely correlated with human cancer. SGK1 is considered a canonical factor affecting the expression and signal transduction of multiple genes involved in the genesis and development of many human cancers. Abnormal expression of SGK1 has been found in tissue and may hopefully become a useful indicator of cancer progression. In addition, SGK1 acts as a prognostic factor for cancer patient survival. This review systematically summarizes and discusses the role of SGK1 as a diagnostic and prognostic biomarker of diverse cancer types; focuses on its essential roles and functions in tumorigenesis, cancer cell proliferation, apoptosis, invasion, metastasis, autophagy, metabolism, and therapy resistance and in the tumor microenvironment; and finally summarizes the current understanding of the regulatory mechanisms of SGK1 at the molecular level. Taken together, this evidence highlights the crucial role of SGK1 in tumorigenesis and cancer progression, revealing why it has emerged as a potential target for cancer therapy.
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Affiliation(s)
- Yiwen Sang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Piaoping Kong
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Shizhen Zhang
- The Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingyu Zhang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Cao
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xiuzhi Duan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Tao Sun
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zhihua Tao
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Weiwei Liu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Feng Y, Chen X, Cassady K, Zou Z, Yang S, Wang Z, Zhang X. The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside. Front Oncol 2021; 10:611690. [PMID: 33489922 PMCID: PMC7821787 DOI: 10.3389/fonc.2020.611690] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/27/2020] [Indexed: 02/05/2023] Open
Abstract
The mTOR pathway plays a central role in many cellular processes, such as cellular growth, protein synthesis, glucose, and lipid metabolism. Aberrant regulation of mTOR is a hallmark of many cancers, including hematological malignancies. mTOR inhibitors, such as Rapamycin and Rapamycin analogs (Rapalogs), have become a promising class of agents to treat malignant blood diseases-either alone or in combination with other treatment regimens. This review highlights experimental evidence underlying the molecular mechanisms of mTOR inhibitors and summarizes their evolving role in the treatment of hematologic disease, including leukemia, lymphoma, myeloma, immune hemocytopenia, and graft-versus-host disease (GVHD). Based on data presented in this review, we believe that mTOR inhibitors are becoming a trusted therapeutic in the clinical hematologist's toolbelt and should be considered more routinely in combination therapy for the management of hematologic disease.
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Affiliation(s)
- Yimei Feng
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
- Chongqing Sub-center of National Clinical Research Center for Hematologic Disease, Chongqing, China
| | - Xiaoli Chen
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
- Chongqing Sub-center of National Clinical Research Center for Hematologic Disease, Chongqing, China
| | - Kaniel Cassady
- Irell and Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA, United States
| | - Zhongmin Zou
- Department of Chemical Defense Medicine, School of Military Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Shijie Yang
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
- Chongqing Sub-center of National Clinical Research Center for Hematologic Disease, Chongqing, China
| | - Zheng Wang
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
- Chongqing Sub-center of National Clinical Research Center for Hematologic Disease, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, The Xinqiao Hospital of Third Military Medical University, Chongqing, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China
- Chongqing Sub-center of National Clinical Research Center for Hematologic Disease, Chongqing, China
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Amino Acids in Cell Signaling: Regulation and Function. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1332:17-33. [PMID: 34251636 DOI: 10.1007/978-3-030-74180-8_2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Amino acids are the main building blocks for life. Aside from their roles in composing proteins, functional amino acids and their metabolites play regulatory roles in key metabolic cascades, gene expressions, and cell-to-cell communication via a variety of cell signaling pathways. These metabolic networks are necessary for maintenance, growth, reproduction, and immunity in humans and animals. These amino acids include, but are not limited to, arginine, glutamine, glutamate, glycine, leucine, proline, and tryptophan. We will discuss these functional amino acids in cell signaling pathways in mammals with a particular emphasis on mTORC1, AMPK, and MAPK pathways for protein synthesis, nutrient sensing, and anti-inflammatory responses, as well as cell survival, growth, and development.
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Lang F, Rajaxavier J, Singh Y, Brucker SY, Salker MS. The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium. Front Cell Dev Biol 2020; 8:556543. [PMID: 33195190 PMCID: PMC7609842 DOI: 10.3389/fcell.2020.556543] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 09/24/2020] [Indexed: 11/13/2022] Open
Abstract
The serum- and glucocorticoid-inducible kinase 1 (SGK1) is subject to genetic up-regulation by diverse stimulators including glucocorticoids, mineralocorticoids, dehydration, ischemia, radiation and hyperosmotic shock. To become active, the expressed kinase requires phosphorylation, which is accomplished by PI3K/PDK1 and mTOR dependent signaling. SGK1 enhances the expression/activity of various transport proteins including Na+/K+-ATPase as well as ion-, glucose-, and amino acid- carriers in the plasma membrane. SGK1 can further up-regulate diverse ion channels, such as Na+-, Ca2+-, K+- and Cl- channels. SGK1 regulates expression/activity of a wide variety of transcription factors (such as FKHRL1/Foxo3a, β-catenin, NFκB and p53). SGK1 thus contributes to the regulation of transport, glycolysis, angiogenesis, cell survival, immune regulation, cell migration, tissue fibrosis and tissue calcification. In this review we summarized the current findings that SGK1 plays a crucial function in the regulation of endometrial function. Specifically, it plays a dual role in the regulation of endometrial receptivity necessary for implantation and, subsequently in pregnancy maintenance. Furthermore, fetal programming of blood pressure regulation requires maternal SGK1. Underlying mechanisms are, however, still ill-defined and there is a substantial need for additional information to fully understand the role of SGK1 in the orchestration of embryo implantation, embryo survival and fetal programming.
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Affiliation(s)
- Florian Lang
- Department of Physiology, Eberhard-Karls University, Tübingen, Germany
| | - Janet Rajaxavier
- Research Institute of Women’s Health, Eberhard-Karls University, Tübingen, Germany
| | - Yogesh Singh
- Research Institute of Women’s Health, Eberhard-Karls University, Tübingen, Germany
- Institute of Medical Genetics and Applied Genomics, Eberhard-Karls University, Tübingen, Germany
| | - Sara Y. Brucker
- Research Institute of Women’s Health, Eberhard-Karls University, Tübingen, Germany
| | - Madhuri S. Salker
- Research Institute of Women’s Health, Eberhard-Karls University, Tübingen, Germany
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Llano E, Masek T, Gahurova L, Pospisek M, Koncicka M, Jindrova A, Jansova D, Iyyappan R, Roucova K, Bruce AW, Kubelka M, Susor A. Age-related differences in the translational landscape of mammalian oocytes. Aging Cell 2020; 19:e13231. [PMID: 32951297 PMCID: PMC7576272 DOI: 10.1111/acel.13231] [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: 05/12/2020] [Revised: 07/15/2020] [Accepted: 08/01/2020] [Indexed: 12/13/2022] Open
Abstract
Increasing maternal age in mammals is associated with poorer oocyte quality, involving higher aneuploidy rates and decreased developmental competence. Prior to resumption of meiosis, fully developed mammalian oocytes become transcriptionally silent until the onset of zygotic genome activation. Therefore, meiotic progression and early embryogenesis are driven largely by translational utilization of previously synthesized mRNAs. We report that genome‐wide translatome profiling reveals considerable numbers of transcripts that are differentially translated in oocytes obtained from aged compared to young females. Additionally, we show that a number of aberrantly translated mRNAs in oocytes from aged females are associated with cell cycle. Indeed, we demonstrate that four specific maternal age‐related transcripts (Sgk1, Castor1, Aire and Eg5) with differential translation rates encode factors that are associated with the newly forming meiotic spindle. Moreover, we report substantial defects in chromosome alignment and cytokinesis in the oocytes of young females, in which candidate CASTOR1 and SGK1 protein levels or activity are experimentally altered. Our findings indicate that improper translation of specific proteins at the onset of meiosis contributes to increased chromosome segregation problems associated with female ageing.
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Affiliation(s)
- Edgar Llano
- Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics CAS Libechov Czech Republic
- Laboratory of RNA Biochemistry Department of Genetics and Microbiology Faculty of Science Charles University in Prague Prague Czech Republic
| | - Tomas Masek
- Laboratory of RNA Biochemistry Department of Genetics and Microbiology Faculty of Science Charles University in Prague Prague Czech Republic
| | - Lenka Gahurova
- Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics CAS Libechov Czech Republic
- Laboratory of Early Mammalian Developmental Biology (LEMDB) Department of Molecular Biology and Genetics Faculty of Science University of South Bohemia Ceske Budejovice Czech Republic
| | - Martin Pospisek
- Laboratory of RNA Biochemistry Department of Genetics and Microbiology Faculty of Science Charles University in Prague Prague Czech Republic
| | - Marketa Koncicka
- Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics CAS Libechov Czech Republic
| | - Anna Jindrova
- Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics CAS Libechov Czech Republic
| | - Denisa Jansova
- Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics CAS Libechov Czech Republic
| | - Rajan Iyyappan
- Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics CAS Libechov Czech Republic
| | - Kristina Roucova
- Laboratory of RNA Biochemistry Department of Genetics and Microbiology Faculty of Science Charles University in Prague Prague Czech Republic
| | - Alexander W. Bruce
- Laboratory of Early Mammalian Developmental Biology (LEMDB) Department of Molecular Biology and Genetics Faculty of Science University of South Bohemia Ceske Budejovice Czech Republic
| | - Michal Kubelka
- Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics CAS Libechov Czech Republic
| | - Andrej Susor
- Laboratory of Biochemistry and Molecular Biology of Germ Cells Institute of Animal Physiology and Genetics CAS Libechov Czech Republic
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Maiese K. Dysregulation of metabolic flexibility: The impact of mTOR on autophagy in neurodegenerative disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2020; 155:1-35. [PMID: 32854851 DOI: 10.1016/bs.irn.2020.01.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Non-communicable diseases (NCDs) that involve neurodegenerative disorders and metabolic disease impact over 400 million individuals globally. Interestingly, metabolic disorders, such as diabetes mellitus, are significant risk factors for the development of neurodegenerative diseases. Given that current therapies for these NCDs address symptomatic care, new avenues of discovery are required to offer treatments that affect disease progression. Innovative strategies that fill this void involve the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), AMP activated protein kinase (AMPK), trophic factors that include erythropoietin (EPO), and the programmed cell death pathways of autophagy and apoptosis. These pathways are intriguing in their potential to provide effective care for metabolic and neurodegenerative disorders. Yet, future work is necessary to fully comprehend the entire breadth of the mTOR pathways that can effectively and safely translate treatments to clinical medicine without the development of unexpected clinical disabilities.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY, United States.
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32
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Phosphoproteomics reveals that the hVPS34 regulated SGK3 kinase specifically phosphorylates endosomal proteins including Syntaxin-7, Syntaxin-12, RFIP4 and WDR44. Biochem J 2020; 476:3081-3107. [PMID: 31665227 PMCID: PMC6824681 DOI: 10.1042/bcj20190608] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 10/02/2019] [Accepted: 10/03/2019] [Indexed: 01/04/2023]
Abstract
The serum- and glucocorticoid-regulated kinase (SGK) isoforms contribute resistance to cancer therapies targeting the PI3K pathway. SGKs are homologous to Akt and these kinases display overlapping specificity and phosphorylate several substrates at the same residues, such as TSC2 to promote tumor growth by switching on the mTORC1 pathway. The SGK3 isoform is up-regulated in breast cancer cells treated with PI3K or Akt inhibitors and recruited and activated at endosomes, through its phox homology domain binding to PtdIns(3)P. We undertook genetic and pharmacological phosphoproteomic screens to uncover novel SGK3 substrates. We identified 40 potential novel SGK3 substrates, including four endosomal proteins STX7 (Ser126) and STX12 (Ser139), RFIP4 (Ser527) and WDR44 (Ser346) that were efficiently phosphorylated in vitro by SGK3 at the sites identified in vivo, but poorly by Akt. We demonstrate that these substrates are inefficiently phosphorylated by Akt as they possess an n + 1 residue from the phosphorylation site that is unfavorable for Akt phosphorylation. Phos-tag analysis revealed that stimulation of HEK293 cells with IGF1 to activate SGK3, promoted phosphorylation of a significant fraction of endogenous STX7 and STX12, in a manner that was blocked by knock-out of SGK3 or treatment with a pan SGK inhibitor (14H). SGK3 phosphorylation of STX12 enhanced interaction with the VAMP4/VTI1A/STX6 containing the SNARE complex and promoted plasma membrane localization. Our data reveal novel substrates for SGK3 and suggest a mechanism by which STX7 and STX12 SNARE complexes are regulated by SGK3. They reveal new biomarkers for monitoring SGK3 pathway activity.
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33
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Qian J, Su S, Liu P. Experimental Approaches in Delineating mTOR Signaling. Genes (Basel) 2020; 11:E738. [PMID: 32630768 PMCID: PMC7397015 DOI: 10.3390/genes11070738] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 06/28/2020] [Accepted: 06/30/2020] [Indexed: 11/16/2022] Open
Abstract
The mTOR signaling controls essential biological functions including proliferation, growth, metabolism, autophagy, ageing, and others. Hyperactivation of mTOR signaling leads to a plethora of human disorders; thus, mTOR is an attractive drug target. The discovery of mTOR signaling started from isolation of rapamycin in 1975 and cloning of TOR genes in 1993. In the past 27 years, numerous research groups have contributed significantly to advancing our understanding of mTOR signaling and mTOR biology. Notably, a variety of experimental approaches have been employed in these studies to identify key mTOR pathway members that shape up the mTOR signaling we know today. Technique development drives mTOR research, while canonical biochemical and yeast genetics lay the foundation for mTOR studies. Here in this review, we summarize major experimental approaches used in the past in delineating mTOR signaling, including biochemical immunoprecipitation approaches, genetic approaches, immunofluorescence microscopic approaches, hypothesis-driven studies, protein sequence or motif search driven approaches, and bioinformatic approaches. We hope that revisiting these distinct types of experimental approaches will provide a blueprint for major techniques driving mTOR research. More importantly, we hope that thinking and reasonings behind these experimental designs will inspire future mTOR research as well as studies of other protein kinases beyond mTOR.
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Affiliation(s)
- Jiayi Qian
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (J.Q.); (S.S.)
- Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Siyuan Su
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (J.Q.); (S.S.)
- Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Pengda Liu
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; (J.Q.); (S.S.)
- Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Abstract
Metabolic disorders, such as diabetes mellitus (DM), are increasingly becoming significant risk factors for the health of the global population and consume substantial portions of the gross domestic product of all nations. Although conventional therapies that include early diagnosis, nutritional modification of diet, and pharmacological treatments may limit disease progression, tight serum glucose control cannot prevent the onset of future disease complications. With these concerns, novel strategies for the treatment of metabolic disorders that involve the vitamin nicotinamide, the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and the cellular pathways of autophagy and apoptosis offer exceptional promise to provide new avenues of treatment. Oversight of these pathways can promote cellular energy homeostasis, maintain mitochondrial function, improve glucose utilization, and preserve pancreatic beta-cell function. Yet, the interplay among mTOR, AMPK, and autophagy pathways can be complex and affect desired clinical outcomes, necessitating further investigations to provide efficacious treatment strategies for metabolic dysfunction and DM.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022,
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Prossomariti A, Piazzi G, Alquati C, Ricciardiello L. Are Wnt/β-Catenin and PI3K/AKT/mTORC1 Distinct Pathways in Colorectal Cancer? Cell Mol Gastroenterol Hepatol 2020; 10:491-506. [PMID: 32334125 PMCID: PMC7369353 DOI: 10.1016/j.jcmgh.2020.04.007] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 04/05/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023]
Abstract
Wnt/β-catenin and phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin complex 1 (PI3K/AKT/mTORC1) pathways both are critically involved in colorectal cancer (CRC) development, although they are implicated in the modulation of distinct oncogenic mechanisms. In homeostatic and pathologic conditions, these pathways show a fine regulation based mainly on feedback mechanisms, and are connected at multiple levels involving both upstream and downstream common effectors. The ability of the Wnt/β-catenin and PI3K/AKT/mTORC1 pathways to reciprocally control themselves represents one of the main resistance mechanisms to selective inhibitors in CRC, leading to the hypothesis that in specific settings, particularly in cancer driven by genetic alterations in Wnt/β-catenin signaling, the relationship between Wnt/β-catenin and PI3K/AKT/mTORC1 pathways could be so close that they should be considered as a unique therapeutic target. This review provides an update on the Wnt/β-catenin and PI3K/AKT/mTORC1 pathway interconnections in CRC, describing the main molecular players and the potential implications of combined inhibitors as an approach for CRC chemoprevention and treatment.
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Affiliation(s)
- Anna Prossomariti
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Center for Applied Biomedical Research, S. Orsola Hospital, University of Bologna, Bologna, Italy,Anna Prossomariti, PhD, Center for Applied Biomedical Research, S. Orsola Hospital, Via Massarenti 9, 40138, Bologna, Italy. fax: (39) 051-2143902.
| | - Giulia Piazzi
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Center for Applied Biomedical Research, S. Orsola Hospital, University of Bologna, Bologna, Italy
| | - Chiara Alquati
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Center for Applied Biomedical Research, S. Orsola Hospital, University of Bologna, Bologna, Italy
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy,Center for Applied Biomedical Research, S. Orsola Hospital, University of Bologna, Bologna, Italy,Correspondence Address correspondence to: Luigi Ricciardiello, MD, Department of Medical and Surgical Sciences, Via Massarenti 9, 40138, Bologna, Italy. fax: (39) 051-2143381
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Venugopal SV, Caggia S, Gambrell-Sanders D, Khan SA. Differential roles and activation of mammalian target of rapamycin complexes 1 and 2 during cell migration in prostate cancer cells. Prostate 2020; 80:412-423. [PMID: 31995655 PMCID: PMC7232714 DOI: 10.1002/pros.23956] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 01/15/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Mammalian target of rapamycin (mTOR) is a downstream substrate activated by PI3K/AKT pathway and it is essential for cell migration. It exists as two complexes: mTORC1 and mTORC2. mTORC1 is known to be regulated by active AKT, but the activation of mTORC2 is poorly understood. In this study, we investigated the roles and differential activation of the two mTOR complexes during cell migration in prostate cancer cells. METHODS We used small interfering RNA to silence the expression of Rac1 and the main components of mTOR complexes (regulatory associated protein of mTOR [RAPTOR] and rapamycin-insensitive companion of mTOR [RICTOR]) in LNCaP, DU145, and PC3 prostate cancer cell lines. We performed transwell migration assay to evaluate the migratory capability of the cells, and Western blot analysis to study the activation levels of mTOR complexes. RESULTS Specific knockdown of RAPTOR and RICTOR caused a decrease of cell migration, suggesting their essential role in prostate cancer cell movement. Furthermore, epidermal growth factor (EGF) treatments induced the activation of both the mTOR complexes. Lack of Rac1 activity in prostate cancer cells blocked EGF-induced activation of mTORC2, but had no effect on mTORC1 activation. Furthermore, the overexpression of constitutively active Rac1 resulted in significant increase in cell migration and activation of mTORC2 in PC3 cells, but had no effect on mTORC1 activation. Active Rac1 was localized in the plasma membrane and was found to be in a protein complex, with RICTOR, but not RAPTOR. CONCLUSION We suggest that EGF-induced activation of Rac1 causes the activation of mTORC2 via RICTOR. This mechanism plays a critical role in prostate cancer cell migration.
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Affiliation(s)
- Smrruthi Vaidegi Venugopal
- Department of biological sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Silvia Caggia
- Department of biological sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - DaJhnae Gambrell-Sanders
- Department of biological sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
| | - Shafiq A Khan
- Department of biological sciences, Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, Georgia
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Zhang Z, Xu Q, Song C, Mi B, Zhang H, Kang H, Liu H, Sun Y, Wang J, Lei Z, Guan H, Li F. Serum- and Glucocorticoid-inducible Kinase 1 is Essential for Osteoclastogenesis and Promotes Breast Cancer Bone Metastasis. Mol Cancer Ther 2020; 19:650-660. [PMID: 31694887 DOI: 10.1158/1535-7163.mct-18-0783] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 12/30/2018] [Accepted: 10/31/2019] [Indexed: 11/16/2022]
Abstract
Bone metastasis is a severe complication associated with various carcinomas. It causes debilitating pain and pathologic fractures and dramatically impairs patients' quality of life. Drugs aimed at osteoclast formation significantly reduce the incidence of skeletal complications and are currently the standard treatment for patients with bone metastases. Here, we reported that serum- and glucocorticoid-inducible kinase 1 (SGK1) plays a pivotal role in the formation and function of osteoclasts by regulating the Ca2+ release-activated Ca2+ channel Orai1. We showed that SGK1 inhibition represses osteoclastogenesis in vitro and prevents bone loss in vivo Furthermore, we validated the effect of SGK1 on bone metastasis by using an intracardiac injection model in mice. Inhibition of SGK1 resulted in a significant reduction in bone metastasis. Subsequently, the Oncomine and the OncoLnc database were employed to verify the differential expression and the association with clinical outcome of SGK1 gene in patients with breast cancer. Our data mechanistically demonstrated the regulation of the SGK1 in the process of osteoclastogenesis and revealed SGK1 as a valuable target for curing bone metastasis diseases.
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Affiliation(s)
- Zheng Zhang
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Qian Xu
- Department of Hematology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chao Song
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Baoguo Mi
- Department of Spine Surgery, Honghui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, China
| | - Honghua Zhang
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Honglei Kang
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huiyong Liu
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yunlong Sun
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jia Wang
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhuowei Lei
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hanfeng Guan
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China.
| | - Feng Li
- Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, China.
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Maiese K. The Mechanistic Target of Rapamycin (mTOR): Novel Considerations as an Antiviral Treatment. Curr Neurovasc Res 2020; 17:332-337. [PMID: 32334502 PMCID: PMC7541431 DOI: 10.2174/1567202617666200425205122] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 04/12/2020] [Accepted: 04/16/2020] [Indexed: 02/07/2023]
Abstract
Multiple viral pathogens can pose a significant health risk to individuals. As a recent example, the β-coronavirus family virion, SARS-CoV-2, has quickly evolved as a pandemic leading to coronavirus disease 2019 (COVID-19) and has been declared by the World Health Organization as a Public Health Emergency of International Concern. To date, no definitive treatment or vaccine application exists for COVID-19. Although new investigations seek to repurpose existing antiviral treatments for COVID-19, innovative treatment strategies not normally considered to have antiviral capabilities may be critical to address this global concern. One such avenue that may prove to be exceedingly fruitful and offer exciting potential as new antiviral therapy involves the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), and AMP activated protein kinase (AMPK). Recent work has shown that mTOR pathways in conjunction with AMPK may offer valuable targets to control cell injury, oxidative stress, mitochondrial dysfunction, and the onset of hyperinflammation, a significant disability associated with COVID-19. Furthermore, pathways that can activate mTOR may be necessary for anti-hepatitis C activity, reduction of influenza A virus replication, and vital for type-1 interferon responses with influenza vaccination. Yet, important considerations for the development of safe and effective antiviral therapy with mTOR pathways exist. Under some conditions, mTOR can act as a double edge sword and participate in virion replication and virion release from cells. Future work with mTOR as a potential antiviral target is highly warranted and with a greater understanding of this novel pathway, new treatments against several viral pathogens may successfully emerge.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY10022, USA
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Knudsen JR, Fritzen AM, James DE, Jensen TE, Kleinert M, Richter EA. Growth Factor-Dependent and -Independent Activation of mTORC2. Trends Endocrinol Metab 2020; 31:13-24. [PMID: 31699566 DOI: 10.1016/j.tem.2019.09.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 08/19/2019] [Accepted: 09/12/2019] [Indexed: 01/03/2023]
Abstract
The target of rapamycin complex 2 (TORC2) was discovered in 2002 in budding yeast. Its mammalian counterpart, mTORC2, was first described in 2004. Soon thereafter it was demonstrated that mTORC2 directly phosphorylates Akt on Ser473, ending a long search for the elusive 'second' insulin-responsive Akt kinase. In this review we discuss key evidence pertaining to the subcellular localization of mTORC2, highlighting a spatial heterogeneity that relates to mTORC2 activation. We summarize current models for how growth factors (GFs), such as insulin, trigger mTORC2 activation, and we provide a comprehensive discussion focusing on a new exciting frontier, the molecular mechanisms underpinning GF-independent activation of mTORC2.
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Affiliation(s)
- Jonas R Knudsen
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Andreas M Fritzen
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - David E James
- School of Life and Environmental Sciences and Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia
| | - Thomas E Jensen
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Maximilian Kleinert
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark; Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum Muenchen & German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Erik A Richter
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
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Maiese K. Nicotinamide: Oversight of Metabolic Dysfunction Through SIRT1, mTOR, and Clock Genes. Curr Neurovasc Res 2020; 17:765-783. [PMID: 33183203 PMCID: PMC7914159 DOI: 10.2174/1567202617999201111195232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 10/24/2020] [Accepted: 10/27/2020] [Indexed: 12/13/2022]
Abstract
Metabolic disorders that include diabetes mellitus present significant challenges for maintaining the welfare of the global population. Metabolic diseases impact all systems of the body and despite current therapies that offer some protection through tight serum glucose control, ultimately such treatments cannot block the progression of disability and death realized with metabolic disorders. As a result, novel therapeutic avenues are critical for further development to address these concerns. An innovative strategy involves the vitamin nicotinamide and the pathways associated with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and clock genes. Nicotinamide maintains an intimate relationship with these pathways to oversee metabolic disease and improve glucose utilization, limit mitochondrial dysfunction, block oxidative stress, potentially function as antiviral therapy, and foster cellular survival through mechanisms involving autophagy. However, the pathways of nicotinamide, SIRT1, mTOR, AMPK, and clock genes are complex and involve feedback pathways as well as trophic factors such as erythropoietin that require a careful balance to ensure metabolic homeostasis. Future work is warranted to gain additional insight into these vital pathways that can oversee both normal metabolic physiology and metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev Clin Pharmacol 2020; 13:23-34. [PMID: 31794280 PMCID: PMC6959472 DOI: 10.1080/17512433.2020.1698288] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
Abstract
Introduction: Dementia is the 7th leading cause of death that imposes a significant financial and service burden on the global population. Presently, only symptomatic care exists for cognitive loss, such as Alzheimer's disease.Areas covered: Given the advancing age of the global population, it becomes imperative to develop innovative therapeutic strategies for cognitive loss. New studies provide insight to the association of cognitive loss with metabolic disorders, such as diabetes mellitus.Expert opinion: Diabetes mellitus is increasing in incidence throughout the world and affects 350 million individuals. Treatment strategies identifying novel pathways that oversee metabolic and neurodegenerative disorders offer exciting prospects to treat dementia. The mechanistic target of rapamycin (mTOR) and circadian clock gene pathways that include AMP activated protein kinase (AMPK), Wnt1 inducible signaling pathway protein 1 (WISP1), erythropoietin (EPO), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) provide novel strategies to treat cognitive loss that has its basis in metabolic cellular dysfunction. However, these pathways are complex and require precise regulation to maximize treatment efficacy and minimize any potential clinical disability. Further investigations hold great promise to treat both the onset and progression of cognitive loss that is associated with metabolic disease.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, New York 10022
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Wang H, Liu Y, Wang D, Xu Y, Dong R, Yang Y, Lv Q, Chen X, Zhang Z. The Upstream Pathway of mTOR-Mediated Autophagy in Liver Diseases. Cells 2019; 8:E1597. [PMID: 31835352 PMCID: PMC6953127 DOI: 10.3390/cells8121597] [Citation(s) in RCA: 187] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/29/2019] [Accepted: 12/03/2019] [Indexed: 12/11/2022] Open
Abstract
Autophagy, originally found in liver experiments, is a cellular process that degrades damaged organelle or protein aggregation. This process frees cells from various stress states is a cell survival mechanism under stress stimulation. It is now known that dysregulation of autophagy can cause many liver diseases. Therefore, how to properly regulate autophagy is the key to the treatment of liver injury. mechanistic target of rapamycin (mTOR)is the core hub regulating autophagy, which is subject to different upstream signaling pathways to regulate autophagy. This review summarizes three upstream pathways of mTOR: the phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) signaling pathway, the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, and the rat sarcoma (Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen-extracellular activated protein kinase kinase (MEK)/ extracellular-signal-regulated kinase (ERK) signaling pathway, specifically explored their role in liver fibrosis, hepatitis B, non-alcoholic fatty liver, liver cancer, hepatic ischemia reperfusion and other liver diseases through the regulation of mTOR-mediated autophagy. Moreover, we also analyzed the crosstalk between these three pathways, aiming to find new targets for the treatment of human liver disease based on autophagy.
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Affiliation(s)
- Haojie Wang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Yumei Liu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Dongmei Wang
- College of Medical, Henan University of Science and Technology, Luoyang 471000, China;
| | - Yaolu Xu
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Ruiqi Dong
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Yuxiang Yang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Qiongxia Lv
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Xiaoguang Chen
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
| | - Ziqiang Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471000, China; (H.W.); (Y.X.); (R.D.); (Y.Y.); (Q.L.); (X.C.)
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Kumar V, Evans LC, Kurth T, Yang C, Wollner C, Nasci V, Zheleznova NN, Bukowy J, Dayton A, Cowley AW. Therapeutic Suppression of mTOR (Mammalian Target of Rapamycin) Signaling Prevents and Reverses Salt-Induced Hypertension and Kidney Injury in Dahl Salt-Sensitive Rats. Hypertension 2019; 73:630-639. [PMID: 30595123 DOI: 10.1161/hypertensionaha.118.12378] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
mTOR (mammalian target of rapamycin) signaling has emerged as a key regulator in a wide range of cellular processes ranging from cell proliferation, immune responses, and electrolyte homeostasis. mTOR consists of 2 distinct protein complexes, mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) with distinct downstream signaling events. mTORC1 has been implicated in pathological conditions, such as cancer and type 2 diabetes mellitus in humans, and inhibition of this pathway with rapamycin has been shown to attenuate salt-induced hypertension in Dahl salt-sensitive rats. Several studies have found that the mTORC2 pathway is involved in the regulation of renal tubular sodium and potassium transport, but its role in hypertension has remained largely unexplored. In the present study, we, therefore, determined the effect of mTORC2 inhibition with compound PP242 on salt-induced hypertension and renal injury in salt-sensitive rats. We found that PP242 not only completely prevented but also reversed salt-induced hypertension and kidney injury in salt-sensitive rats. PP242 exhibited potent natriuretic actions, and chronic administration tended to produce a negative Na+ balance even during high-salt feeding. The results indicate that mTORC2 and the related downstream associated pathways play an important role in regulation of sodium balance and arterial pressure regulation in salt-sensitive rats. Therapeutic suppression of the mTORC2 pathway represents a novel pathway for the potential treatment of hypertension.
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Affiliation(s)
- Vikash Kumar
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | - Louise C Evans
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | - Theresa Kurth
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | - Chun Yang
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | - Clayton Wollner
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | - Victoria Nasci
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | | | - John Bukowy
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | - Alex Dayton
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
| | - Allen W Cowley
- From the Department of Physiology, Medical College of Wisconsin, Milwaukee
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The Emerging Roles of mTORC1 in Macromanaging Autophagy. Cancers (Basel) 2019; 11:cancers11101422. [PMID: 31554253 PMCID: PMC6826502 DOI: 10.3390/cancers11101422] [Citation(s) in RCA: 205] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 09/22/2019] [Accepted: 09/23/2019] [Indexed: 01/18/2023] Open
Abstract
Autophagy is a process of self-degradation that enables the cell to survive when faced with starvation or stressful conditions. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, plays a critical role in maintaining a balance between cellular anabolism and catabolism. mTOR complex 1 (mTORC1) was unveiled as a master regulator of autophagy since inhibition of mTORC1 was required to initiate the autophagy process. Evidence has emerged in recent years to indicate that mTORC1 also directly regulates the subsequent steps of the autophagy process, including the nucleation, autophagosome elongation, autophagosome maturation and termination. By phosphorylating select protein targets of the autophagy core machinery and/or their regulators, mTORC1 can alter their functions, increase their proteasomal degradation or modulate their acetylation status, which is a key switch of the autophagy process. Moreover, it phosphorylates and alters the subcellular localization of transcription factors to suppress the expression of genes needed for autophagosome formation and lysosome biogenesis. The purpose of this review article is to critically analyze current literatures to provide an integrated view of how mTORC1 regulates various steps of the autophagy process.
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Estradiol promotes trophoblast viability and invasion by activating SGK1. Biomed Pharmacother 2019; 117:109092. [DOI: 10.1016/j.biopha.2019.109092] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 05/24/2019] [Accepted: 06/04/2019] [Indexed: 01/02/2023] Open
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Sørensen MV, Saha B, Jensen IS, Wu P, Ayasse N, Gleason CE, Svendsen SL, Wang WH, Pearce D. Potassium acts through mTOR to regulate its own secretion. JCI Insight 2019; 5:126910. [PMID: 31013253 DOI: 10.1172/jci.insight.126910] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Potassium (K+) secretion by kidney tubule cells is central to electrolyte homeostasis in mammals. In the K+ secretory "principal" cells of the distal nephron, electrogenic Na+ transport by the epithelial sodium channel (ENaC) generates the electrical driving force for K+ transport across the apical membrane. Regulation of this process is attributable in part to aldosterone, which stimulates the gene transcription of the ENaC-regulatory kinase, SGK1. However, a wide range of evidence supports the conclusion that an unidentified aldosterone-independent pathway exists. We show here that in principal cells, K+ itself acts through the type 2 mTOR complex (mTORC2) to activate SGK1, which stimulates ENaC to enhance K+ excretion. The effect depends on changes in K+ concentration on the blood side of the cells, and requires basolateral membrane K+-channel activity. However, it does not depend on changes in aldosterone, or on enhanced distal delivery of Na+ from upstream nephron segments. These data strongly support the idea that K+ is sensed directly by principal cells to stimulate its own secretion by activating the mTORC2-SGK1 signaling module, and stimulate ENaC. We propose that this local effect acts in concert with aldosterone and increased Na+ delivery from upstream nephron segments to sustain K+ homeostasis.
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Affiliation(s)
- Mads Vaarby Sørensen
- Departments of Biomedicine and Physiology, Aarhus University, Aarhus, Denmark.,Aarhus Institute for Advanced Studies, Aarhus University, Aarhus, Denmark
| | - Bidisha Saha
- Department of Medicine, Division of Nephrology, and Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California, USA
| | - Iben Skov Jensen
- Departments of Biomedicine and Physiology, Aarhus University, Aarhus, Denmark
| | - Peng Wu
- Department of Pharmacology, New York Medical College, Valhalla, New York, USA
| | - Niklas Ayasse
- Departments of Biomedicine and Physiology, Aarhus University, Aarhus, Denmark
| | - Catherine E Gleason
- Department of Medicine, Division of Nephrology, and Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California, USA
| | | | - Wen-Hui Wang
- Department of Pharmacology, New York Medical College, Valhalla, New York, USA
| | - David Pearce
- Department of Medicine, Division of Nephrology, and Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California, USA
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Chiarini F, Evangelisti C, Lattanzi G, McCubrey JA, Martelli AM. Advances in understanding the mechanisms of evasive and innate resistance to mTOR inhibition in cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:1322-1337. [PMID: 30928610 DOI: 10.1016/j.bbamcr.2019.03.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/22/2019] [Accepted: 03/26/2019] [Indexed: 12/12/2022]
Abstract
The development of drug-resistance by neoplastic cells is recognized as a major cause of targeted therapy failure and disease progression. The mechanistic (previously mammalian) target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that acts as the catalytic subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. Both mTORC1 and mTORC2 play key roles in a variety of healthy cell types/tissues by regulating physiological anabolic and catabolic processes in response to external cues. However, a body of evidence identified aberrant activation of mTOR signaling as a common event in many human tumors. Therefore, mTOR is an attractive target for therapeutic targeting in cancer and this fact has driven the development of numerous mTOR inhibitors, several of which have progressed to clinical trials. Nevertheless, mTOR inhibitors have met with a very limited success as anticancer therapeutics. Among other reasons, this failure was initially ascribed to the activation of several compensatory signaling pathways that dampen the efficacy of mTOR inhibitors. The discovery of these regulatory feedback mechanisms greatly contributed to a better understanding of cancer cell resistance to mTOR targeting agents. However, over the last few years, other mechanisms of resistance have emerged, including epigenetic alterations, compensatory metabolism rewiring and the occurrence of mTOR mutations. In this article, we provide the reader with an updated overview of the mechanisms that could explain resistance of cancer cells to the various classes of mTOR inhibitors.
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Affiliation(s)
- Francesca Chiarini
- CNR Institute of Molecular Genetics, 40136 Bologna, BO, Italy; IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, BO, Italy
| | - Camilla Evangelisti
- CNR Institute of Molecular Genetics, 40136 Bologna, BO, Italy; IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, BO, Italy
| | - Giovanna Lattanzi
- CNR Institute of Molecular Genetics, 40136 Bologna, BO, Italy; IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, BO, Italy
| | - James A McCubrey
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
| | - Alberto M Martelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, BO, Italy.
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Gurska LM, Ames K, Gritsman K. Signaling Pathways in Leukemic Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1143:1-39. [PMID: 31338813 PMCID: PMC7249489 DOI: 10.1007/978-981-13-7342-8_1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) utilize many of the same signaling pathways for their maintenance and survival. In this review, we will focus on several signaling pathways whose roles have been extensively studied in both HSCs and LSCs. Our main focus will be on the PI3K/AKT/mTOR pathway and several of its regulators and downstream effectors. We will also discuss several other signaling pathways of particular importance in LSCs, including the WNT/β-catenin pathway, the NOTCH pathway, and the TGFβ pathway. For each of these pathways, we will emphasize differences in how these pathways operate in LSCs, compared to their function in HSCs, to highlight opportunities for the specific therapeutic targeting of LSCs. We will also highlight areas of crosstalk between multiple signaling pathways that may affect LSC function.
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Affiliation(s)
- Lindsay M Gurska
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Kristina Ames
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Kira Gritsman
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA.
- Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
- Department of Medical Oncology, Montefiore Hospital, Bronx, New York, USA.
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Kamel KS, Schreiber M, Halperin ML. Renal potassium physiology: integration of the renal response to dietary potassium depletion. Kidney Int 2018; 93:41-53. [PMID: 29102372 DOI: 10.1016/j.kint.2017.08.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 07/31/2017] [Accepted: 08/03/2017] [Indexed: 01/30/2023]
Abstract
We summarize the current understanding of the physiology of the renal handling of potassium (K+), and present an integrative view of the renal response to K+ depletion caused by dietary K+ restriction. This renal response involves contributions from different nephron segments, and aims to diminish the rate of excretion of K+ as a result of: decreasing the rate of electrogenic (and increasing the rate of electroneutral) reabsorption of sodium in the aldosterone-sensitive distal nephron (ASDN), decreasing the abundance of renal outer medullary K+ channels in the luminal membrane of principal cells in the ASDN, decreasing the flow rate in the ASDN, and increasing the reabsorption of K+ in the cortical and medullary collecting ducts. The implications of this physiology for the association between K+ depletion and hypertension, and K+ depletion and formation of calcium kidney stones are discussed.
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Affiliation(s)
- Kamel S Kamel
- Renal Division, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
| | - Martin Schreiber
- Renal Division, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Mitchell L Halperin
- Renal Division, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada; Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
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Caron A, Briscoe DM, Richard D, Laplante M. DEPTOR at the Nexus of Cancer, Metabolism, and Immunity. Physiol Rev 2018; 98:1765-1803. [PMID: 29897294 DOI: 10.1152/physrev.00064.2017] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is an important modulator of mTOR, a kinase at the center of two important protein complexes named mTORC1 and mTORC2. These highly studied complexes play essential roles in regulating growth, metabolism, and immunity in response to mitogens, nutrients, and cytokines. Defects in mTOR signaling have been associated with the development of many diseases, including cancer and diabetes, and approaches aiming at modulating mTOR activity are envisioned as an attractive strategy to improve human health. DEPTOR interaction with mTOR represses its kinase activity and rewires the mTOR signaling pathway. Over the last years, several studies have revealed key roles for DEPTOR in numerous biological and pathological processes. Here, we provide the current state of the knowledge regarding the cellular and physiological functions of DEPTOR by focusing on its impact on the mTOR pathway and its role in promoting health and disease.
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Affiliation(s)
- Alexandre Caron
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center , Dallas, Texas ; Transplant Research Program, Boston Children's Hospital , Boston, Massachusetts ; Department of Pediatrics, Harvard Medical School , Boston, Massachusetts ; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval , Québec , Canada ; and Centre de Recherche sur le Cancer de l'Université Laval, Université Laval , Québec , Canada
| | - David M Briscoe
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center , Dallas, Texas ; Transplant Research Program, Boston Children's Hospital , Boston, Massachusetts ; Department of Pediatrics, Harvard Medical School , Boston, Massachusetts ; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval , Québec , Canada ; and Centre de Recherche sur le Cancer de l'Université Laval, Université Laval , Québec , Canada
| | - Denis Richard
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center , Dallas, Texas ; Transplant Research Program, Boston Children's Hospital , Boston, Massachusetts ; Department of Pediatrics, Harvard Medical School , Boston, Massachusetts ; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval , Québec , Canada ; and Centre de Recherche sur le Cancer de l'Université Laval, Université Laval , Québec , Canada
| | - Mathieu Laplante
- Department of Internal Medicine, Division of Hypothalamic Research, The University of Texas Southwestern Medical Center , Dallas, Texas ; Transplant Research Program, Boston Children's Hospital , Boston, Massachusetts ; Department of Pediatrics, Harvard Medical School , Boston, Massachusetts ; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Faculté de Médecine, Université Laval , Québec , Canada ; and Centre de Recherche sur le Cancer de l'Université Laval, Université Laval , Québec , Canada
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