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Saini S, Gurung P. A comprehensive review of sensors of radiation-induced damage, radiation-induced proximal events, and cell death. Immunol Rev 2025; 329:e13409. [PMID: 39425547 PMCID: PMC11742653 DOI: 10.1111/imr.13409] [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] [Indexed: 10/21/2024]
Abstract
Radiation, a universal component of Earth's environment, is categorized into non-ionizing and ionizing forms. While non-ionizing radiation is relatively harmless, ionizing radiation possesses sufficient energy to ionize atoms and disrupt DNA, leading to cell damage, mutation, cancer, and cell death. The extensive use of radionuclides and ionizing radiation in nuclear technology and medical applications has sparked global concern for their capacity to cause acute and chronic illnesses. Ionizing radiation induces DNA damage either directly through strand breaks and base change or indirectly by generating reactive oxygen species (ROS) and reactive nitrogen species (RNS) via radiolysis of water. This damage triggers a complex cellular response involving recognition of DNA damage, cell cycle arrest, DNA repair mechanisms, release of pro-inflammatory cytokines, and cell death. This review focuses on the mechanisms of radiation-induced cellular damage, recognition of DNA damage and subsequent activation of repair processes, and the critical role of the innate immune response in resolution of the injury. Emphasis is placed on pattern recognition receptors (PRRs) and related receptors that detect damage-associated molecular patterns (DAMPs) and initiate downstream signaling pathways. Radiation-induced cell death pathways are discussed in detail. Understanding these processes is crucial for developing strategies to mitigate the harmful effects of radiation and improve therapeutic outcomes.
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Affiliation(s)
- Saurabh Saini
- Inflammation ProgramUniversity of IowaIowa CityIowaUSA
- Department of Internal MedicineUniversity of IowaIowa CityIowaUSA
- Iowa City Veterans Affairs (VA) Medical CenterIowa CityIowaUSA
| | - Prajwal Gurung
- Inflammation ProgramUniversity of IowaIowa CityIowaUSA
- Department of Internal MedicineUniversity of IowaIowa CityIowaUSA
- Iowa City Veterans Affairs (VA) Medical CenterIowa CityIowaUSA
- Interdisciplinary Graduate Program in Human ToxicologyUniversity of IowaIowa CityIowaUSA
- Immunology Graduate ProgramUniversity of IowaIowa CityIowaUSA
- Center for Immunology and Immune Based DiseaseUniversity of IowaIowa CityIowaUSA
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2
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Buitkamp S, Schwalm S, Jakobi K, Ferreiros N, Wünsche C, Zeuzem S, Gulbins E, Sarrazin C, Pfeilschifter J, Grammatikos G. Acid Sphingomyelinase Activation and ROS Generation Potentiate Antiproliferative Effects of Mitomycin in HCC. Int J Mol Sci 2024; 25:12175. [PMID: 39596241 PMCID: PMC11594907 DOI: 10.3390/ijms252212175] [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: 10/20/2024] [Revised: 11/09/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Sphingolipids play a major role in the regulation of hepatocellular apoptosis and proliferation. We have previously identified sphingolipid metabolites as biomarkers of chronic liver disease and hepatocellular carcinoma. Human hepatocellular carcinoma cell lines were transfected with a plasmid vector encoding for acid sphingomyelinase. Overexpressing cells were subsequently treated with mitomycin and cell proliferation, acid sphingomyelinase activity, sphingolipid concentrations, and generation of reactive oxygen species were assessed. The stimulation of acid sphingomyelinase-overexpressing cell lines with mitomycin showed a significant activation of the enzyme (p < 0.001) followed by an accumulation of various ceramide species (p < 0.001) and reactive oxygen radicals (p < 0.001) as compared to control transfected cells. Consequently, a significant reduction in cell proliferation was observed in acid sphingomyelinase-overexpressing cells (p < 0.05) which could be diminished by the simultaneous application of antioxidant agents. Moreover, the application of mitomycin induced significant alterations in mRNA expression levels of ceramidases and sphingosine kinases (p < 0.05). Our data suggest that the overexpression of the acid sphingomyelinase in human hepatoma cell lines enhances the in vitro antiproliferative potential of mitomycin via accumulation of ceramide and reactive oxygen species. The selective activation of acid sphingomyelinase might offer a novel therapeutic approach in the treatment of hepatocellular carcinoma.
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Affiliation(s)
- Sirkka Buitkamp
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany; (S.B.); (S.S.); (K.J.); (C.W.); (J.P.)
- Klinik für Innere Medizin I, Helios Dr. Horst Schmidt Kliniken Wiesbaden, 65199 Wiesbaden, Germany
| | - Stephanie Schwalm
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany; (S.B.); (S.S.); (K.J.); (C.W.); (J.P.)
| | - Katja Jakobi
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany; (S.B.); (S.S.); (K.J.); (C.W.); (J.P.)
- Medizinische Klinik 2/Rheumatologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany
| | - Nerea Ferreiros
- Pharmazentrum Frankfurt, Institut für klinische Pharmakologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany;
- Multidos, 65520 Bad Camberg, Germany
| | - Christin Wünsche
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany; (S.B.); (S.S.); (K.J.); (C.W.); (J.P.)
- GBG Forschungs GmbH, 63263 Neu-Isenburg, Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1/Gastroenterologie und Hepatologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany;
| | - Erich Gulbins
- Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany;
| | - Christoph Sarrazin
- Medizinische Klinik II, St. Josefs-Hospital Wiesbaden, 65189 Wiesbaden, Germany;
| | - Josef Pfeilschifter
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany; (S.B.); (S.S.); (K.J.); (C.W.); (J.P.)
| | - Georgios Grammatikos
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany; (S.B.); (S.S.); (K.J.); (C.W.); (J.P.)
- Medizinische Klinik 1/Gastroenterologie und Hepatologie, Goethe University Hospital, 60590 Frankfurt am Main, Germany;
- St’ Lukes Hospital, 55236 Thessaloniki, Greece
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Dorweiler TF, Singh A, Ganju A, Lydic TA, Glazer LC, Kolesnick RN, Busik JV. Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy. Cell Metab 2024; 36:1521-1533.e5. [PMID: 38718792 PMCID: PMC11222062 DOI: 10.1016/j.cmet.2024.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 03/08/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024]
Abstract
Diabetic retinopathy is a microvascular disease that causes blindness. Using acid sphingomyelinase knockout mice, we reported that ceramide generation is critical for diabetic retinopathy development. Here, in patients with proliferative diabetic retinopathy, we identify vitreous ceramide imbalance with pathologic long-chain C16-ceramides increasing and protective very long-chain C26-ceramides decreasing. C16-ceramides generate pro-inflammatory/pro-apoptotic ceramide-rich platforms on endothelial surfaces. To geo-localize ceramide-rich platforms, we invented a three-dimensional confocal assay and showed that retinopathy-producing cytokines TNFα and IL-1β induce ceramide-rich platform formation on retinal endothelial cells within seconds, with volumes increasing 2-logs, yielding apoptotic death. Anti-ceramide antibodies abolish these events. Furthermore, intravitreal and systemic anti-ceramide antibodies protect from diabetic retinopathy in standardized rodent ischemia reperfusion and streptozotocin models. These data support (1) retinal endothelial ceramide as a diabetic retinopathy treatment target, (2) early-stage therapy of non-proliferative diabetic retinopathy to prevent progression, and (3) systemic diabetic retinopathy treatment; and they characterize diabetic retinopathy as a "ceramidopathy" reversible by anti-ceramide immunotherapy.
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Affiliation(s)
- Tim F Dorweiler
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Vascular Biology Program, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, MA 02113, USA
| | - Arjun Singh
- Memorial Sloan Kettering Cancer Center, Molecular Pharmacology Program, Sloan Kettering Institute New York, New York, NY 10065, USA
| | - Aditya Ganju
- Memorial Sloan Kettering Cancer Center, Molecular Pharmacology Program, Sloan Kettering Institute New York, New York, NY 10065, USA
| | - Todd A Lydic
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
| | - Louis C Glazer
- Vitreo-Retinal Associates, Grand Rapids, MI 49546, USA; Ophthalmology, Michigan State University, East Lansing, MI 48824, USA
| | - Richard N Kolesnick
- Memorial Sloan Kettering Cancer Center, Molecular Pharmacology Program, Sloan Kettering Institute New York, New York, NY 10065, USA.
| | - Julia V Busik
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Biochemistry and Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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Wilkerson JL, Tatum SM, Holland WL, Summers SA. Ceramides are fuel gauges on the drive to cardiometabolic disease. Physiol Rev 2024; 104:1061-1119. [PMID: 38300524 PMCID: PMC11381030 DOI: 10.1152/physrev.00008.2023] [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: 02/14/2023] [Revised: 01/23/2024] [Accepted: 01/25/2024] [Indexed: 02/02/2024] Open
Abstract
Ceramides are signals of fatty acid excess that accumulate when a cell's energetic needs have been met and its nutrient storage has reached capacity. As these sphingolipids accrue, they alter the metabolism and survival of cells throughout the body including in the heart, liver, blood vessels, skeletal muscle, brain, and kidney. These ceramide actions elicit the tissue dysfunction that underlies cardiometabolic diseases such as diabetes, coronary artery disease, metabolic-associated steatohepatitis, and heart failure. Here, we review the biosynthesis and degradation pathways that maintain ceramide levels in normal physiology and discuss how the loss of ceramide homeostasis drives cardiometabolic pathologies. We highlight signaling nodes that sense small changes in ceramides and in turn reprogram cellular metabolism and stimulate apoptosis. Finally, we evaluate the emerging therapeutic utility of these unique lipids as biomarkers that forecast disease risk and as targets of ceramide-lowering interventions that ameliorate disease.
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Affiliation(s)
- Joseph L Wilkerson
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States
| | - Sean M Tatum
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States
| | - William L Holland
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States
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5
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Winters TA, Marzella L, Molinar-Inglis O, Price PW, Han NC, Cohen JE, Wang SJ, Fotenos AF, Sullivan JM, Esker JI, Lapinskas PJ, DiCarlo AL. Gastrointestinal Acute Radiation Syndrome: Mechanisms, Models, Markers, and Medical Countermeasures. Radiat Res 2024; 201:628-646. [PMID: 38616048 PMCID: PMC11658916 DOI: 10.1667/rade-23-00196.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/14/2024] [Indexed: 04/16/2024]
Abstract
There have been a number of reported human exposures to high dose radiation, resulting from accidents at nuclear power plants (e.g., Chernobyl), atomic bombings (Hiroshima and Nagasaki), and mishaps in industrial and medical settings. If absorbed radiation doses are high enough, evolution of acute radiation syndromes (ARS) will likely impact both the bone marrow as well as the gastrointestinal (GI) tract. Damage incurred in the latter can lead to nutrient malabsorption, dehydration, electrolyte imbalance, altered microbiome and metabolites, and impaired barrier function, which can lead to septicemia and death. To prepare for a medical response should such an incident arise, the National Institute of Allergy and Infectious Diseases (NIAID) funds basic and translational research to address radiation-induced GI-ARS, which remains a critical and prioritized unmet need. Areas of interest include identification of targets for damage and mitigation, animal model development, and testing of medical countermeasures (MCMs) to address GI complications resulting from radiation exposure. To appropriately model expected human responses, it is helpful to study analogous disease states in the clinic that resemble GI-ARS, to inform on best practices for diagnosis and treatment, and translate them back to inform nonclinical drug efficacy models. For these reasons, the NIAID partnered with two other U.S. government agencies (the Biomedical Advanced Research and Development Authority, and the Food and Drug Administration), to explore models, biomarkers, and diagnostics to improve understanding of the complexities of GI-ARS and investigate promising treatment approaches. A two-day workshop was convened in August 2022 that comprised presentations from academia, industry, healthcare, and government, and highlighted talks from 26 subject matter experts across five scientific sessions. This report provides an overview of information that was presented during the conference, and important discussions surrounding a broad range of topics that are critical for the research, development, licensure, and use of MCMs for GI-ARS.
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Affiliation(s)
- Thomas A. Winters
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, Maryland
| | - Libero Marzella
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Olivia Molinar-Inglis
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, Maryland
| | - Paul W. Price
- Office of Regulatory Affairs, DAIT, NIAID, NIH, Rockville, Maryland
| | - Nyun Calvin Han
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Jonathan E. Cohen
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Sue-Jane Wang
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Anthony F. Fotenos
- Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, Maryland
| | - Julie M. Sullivan
- Center for Devices for Radiological Health (CDRH), FDA, Silver Spring, Maryland
| | - John I. Esker
- Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC
| | - Paula J. Lapinskas
- Biomedical Advanced Research and Development Authority (BARDA), Office of the Assistant Secretary for Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC
| | - Andrea L. DiCarlo
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, Maryland
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6
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Tamarat R, Satyamitra MM, Benderitter M, DiCarlo AL. Radiation-induced gastrointestinal and cutaneous injuries: understanding models, pathologies, assessments, and clinically accepted practices. Int J Radiat Biol 2024; 100:969-981. [PMID: 38787685 PMCID: PMC11494497 DOI: 10.1080/09553002.2024.2356544] [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: 01/30/2024] [Revised: 04/02/2024] [Accepted: 04/29/2024] [Indexed: 05/26/2024]
Abstract
PURPOSE A U. S. and European joint effort fostering the development of medical countermeasures (MCMs) operable in case of radiological or nuclear emergencies. METHODS Based on the joint engagement between the U.S. National Institute of Allergy and Infectious Diseases (NIAID) and the French Institut de Radioprotection et de Sûreté Nucléaire (IRSN), a Statement of Intent to Collaborate was signed in 2014 and a series of working group meeting were established. In December 2022, the NIAID and IRSN hosted a five-day, U.S./European meeting titled 'Radiation-Induced Cutaneous and Gastrointestinal Injuries: Advances in Understanding Pathologies, Assessment, and Clinically Accepted Practices' in Paris, France. The goals of the meeting were to bring together U.S. and European investigators to explore new research avenues for the medical management of skin and gastrointestinal injuries, including specific diagnostics for each organ system, animal models, and promising medical countermeasures (MCMs) to mitigate radiation damage. There was also an emphasis on exploring additional areas of medicine and response to understand best practices from other emergency scenarios, which could be leveraged to improve radiation preparedness, and the importance of accurate dosimetry in preclinical work. RESULTS Subsequent to the workshop, seven collaborative projects, funded by both organizations, were established on topics ranging from MCMs and predictive biomarkers, and using physical methods to assess cutaneous radiation injuries, to mechanistic studies to understand radiation-induced damage in multiple organ systems. The importance of accurate dosimetry in preclinical works was highlighted and two recently published U.S./European commentaries that focus on the need for dosimetry standardization in the reported literature had their origins in this meeting. This commentary summarizes the workshop and open discussions among academic investigators, industry researchers, and U.S. and IRSN program representatives. CONCLUSIONS Given the substantive progress made due to these interactions, both groups plan to expand out these meetings by incorporating high-level investigators from across the globe, while endeavoring to maintain the informal setting that was conducive to in-depth scientific discussion and enhanced the state of the science in radiation research.
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Affiliation(s)
- Radia Tamarat
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Merriline M. Satyamitra
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology, and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Marc Benderitter
- Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Fontenay-aux-Roses, France
| | - Andrea L. DiCarlo
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology, and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
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Ribeiro CF, Rodrigues S, Bastos DC, Fanelli GN, Pakula H, Foiani M, Zadra G, Loda M. Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition. Sci Signal 2024; 17:eadh1922. [PMID: 38593154 PMCID: PMC11161871 DOI: 10.1126/scisignal.adh1922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/22/2024] [Indexed: 04/11/2024]
Abstract
Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.
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Affiliation(s)
| | | | | | | | - Hubert Pakula
- Weill Cornell Medical College, New York, New York, US
| | | | - Giorgia Zadra
- Institute of Molecular Genetics, National Research Council, Pavia, Italy
| | - Massimo Loda
- Weill Cornell Medical College, New York, New York, US
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White-Gilbertson S, Lu P, Saatci O, Sahin O, Delaney JR, Ogretmen B, Voelkel-Johnson C. Transcriptome analysis of polyploid giant cancer cells and their progeny reveals a functional role for p21 in polyploidization and depolyploidization. J Biol Chem 2024; 300:107136. [PMID: 38447798 PMCID: PMC10979113 DOI: 10.1016/j.jbc.2024.107136] [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: 10/07/2023] [Revised: 02/03/2024] [Accepted: 02/15/2024] [Indexed: 03/08/2024] Open
Abstract
Polyploid giant cancer cells (PGCC) are frequently detected in tumors and are increasingly recognized for their roles in chromosomal instability and associated genome evolution that leads to cancer recurrence. We previously reported that therapy stress promotes polyploidy, and that acid ceramidase plays a role in depolyploidization. In this study, we used an RNA-seq approach to gain a better understanding of the underlying transcriptomic changes that occur as cancer cells progress through polyploidization and depolyploidization. Our results revealed gene signatures that are associated with disease-free and/or overall survival in several cancers and identified the cell cycle inhibitor CDKN1A/p21 as the major hub in PGCC and early progeny. Increased expression of p21 in PGCC was limited to the cytoplasm. We previously demonstrated that the sphingolipid enzyme acid ceramidase is dispensable for polyploidization upon therapy stress but plays a crucial role in depolyploidization. The current study demonstrates that treatment of cells with ceramide is not sufficient for p53-independent induction of p21 and that knockdown of acid ceramidase, which hydrolyzes ceramide, does not interfere with upregulation of p21. In contrast, blocking the expression of p21 with UC2288 prevented the induction of acid ceramidase and inhibited both the formation of PGCC from parental cells as well as the generation of progeny from PGCC. Taken together, our data suggest that p21 functions upstream of acid ceramidase and plays an important role in polyploidization and depolyploidization.
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Affiliation(s)
- Shai White-Gilbertson
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ping Lu
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ozge Saatci
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Ozgur Sahin
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Joe R Delaney
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Besim Ogretmen
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Christina Voelkel-Johnson
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina, USA; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
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Kandouz M. Cell Death, by Any Other Name…. Cells 2024; 13:325. [PMID: 38391938 PMCID: PMC10886887 DOI: 10.3390/cells13040325] [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: 12/31/2023] [Revised: 02/04/2024] [Accepted: 02/06/2024] [Indexed: 02/24/2024] Open
Abstract
Studies trying to understand cell death, this ultimate biological process, can be traced back to a century ago. Yet, unlike many other fashionable research interests, research on cell death is more alive than ever. New modes of cell death are discovered in specific contexts, as are new molecular pathways. But what is "cell death", really? This question has not found a definitive answer yet. Nevertheless, part of the answer is irreversibility, whereby cells can no longer recover from stress or injury. Here, we identify the most distinctive features of different modes of cell death, focusing on the executive final stages. In addition to the final stages, these modes can differ in their triggering stimulus, thus referring to the initial stages. Within this framework, we use a few illustrative examples to examine how intercellular communication factors in the demise of cells. First, we discuss the interplay between cell-cell communication and cell death during a few steps in the early development of multicellular organisms. Next, we will discuss this interplay in a fully developed and functional tissue, the gut, which is among the most rapidly renewing tissues in the body and, therefore, makes extensive use of cell death. Furthermore, we will discuss how the balance between cell death and communication is modified during a pathological condition, i.e., colon tumorigenesis, and how it could shed light on resistance to cancer therapy. Finally, we briefly review data on the role of cell-cell communication modes in the propagation of cell death signals and how this has been considered as a potential therapeutic approach. Far from vainly trying to provide a comprehensive review, we launch an invitation to ponder over the significance of cell death diversity and how it provides multiple opportunities for the contribution of various modes of intercellular communication.
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Affiliation(s)
- Mustapha Kandouz
- Department of Pathology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201, USA;
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
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10
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Molinar-Inglis O, DiCarlo AL, Lapinskas PJ, Rios CI, Satyamitra MM, Silverman TA, Winters TA, Cassatt DR. Radiation-induced multi-organ injury. Int J Radiat Biol 2024; 100:486-504. [PMID: 38166195 PMCID: PMC11874064 DOI: 10.1080/09553002.2023.2295298] [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: 08/30/2023] [Revised: 10/19/2023] [Accepted: 11/15/2023] [Indexed: 01/04/2024]
Abstract
PURPOSE Natural history studies have been informative in dissecting radiation injury, isolating its effects, and compartmentalizing injury based on the extent of exposure and the elapsed time post-irradiation. Although radiation injury models are useful for investigating the mechanism of action in isolated subsyndromes and development of medical countermeasures (MCMs), it is clear that ionizing radiation exposure leads to multi-organ injury (MOI). METHODS The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases partnered with the Biomedical Advanced Research and Development Authority to convene a virtual two-day meeting titled 'Radiation-Induced Multi-Organ Injury' on June 7-8, 2022. Invited subject matter experts presented their research findings in MOI, including study of mechanisms and possible MCMs to address complex radiation-induced injuries. RESULTS This workshop report summarizes key information from each presentation and discussion by the speakers and audience participants. CONCLUSIONS Understanding the mechanisms that lead to radiation-induced MOI is critical to advancing candidate MCMs that could mitigate the injury and reduce associated morbidity and mortality. The observation that some of these mechanisms associated with MOI include systemic injuries, such as inflammation and vascular damage, suggests that MCMs that address systemic pathways could be effective against multiple organ systems.
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Affiliation(s)
- Olivia Molinar-Inglis
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Andrea L. DiCarlo
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Paula J. Lapinskas
- Biomedical Advanced Research and Development Authority (BARDA), Administration for Strategic Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC, USA
| | - Carmen I. Rios
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Merriline M. Satyamitra
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - Toby A. Silverman
- Biomedical Advanced Research and Development Authority (BARDA), Administration for Strategic Preparedness and Response (ASPR), Department of Health and Human Services (HHS), Washington, DC, USA
| | - Thomas A. Winters
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
| | - David R. Cassatt
- Radiation and Nuclear Countermeasures Program (RNCP), Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Rockville, MD, USA
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11
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Moggio M, Faramarzi B, Portaccio M, Manti L, Lepore M, Diano N. A Sphingolipidomic Profiling Approach for Comparing X-ray-Exposed and Unexposed HepG2 Cells. Int J Mol Sci 2023; 24:12364. [PMID: 37569739 PMCID: PMC10418425 DOI: 10.3390/ijms241512364] [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: 07/03/2023] [Revised: 07/27/2023] [Accepted: 07/30/2023] [Indexed: 08/13/2023] Open
Abstract
An analytical method based on tandem mass spectrometry-shotgun is presently proposed to obtain sphingolipidomic profiles useful for the characterization of lipid extract from X-ray-exposed and unexposed hepatocellular carcinoma cells (HepG2). To obtain a targeted lipidic profile from a specific biological system, the best extraction method must be identified before instrumental analysis. Accordingly, four different classic lipid extraction protocols were compared in terms of efficiency, specificity, and reproducibility. The performance of each procedure was evaluated using the Fourier-transform infrared spectroscopic technique; subsequently, the quality of extracts was estimated using electrospray ionization tandem mass spectrometry. The selected procedure based on chloroform/methanol/water was successfully used in mass spectrometry-based shotgun sphingolipidomics, allowing for evaluation of the response of cells to X-ray irradiation, the most common anticancer therapy. Using a relative quantitative approach, the changes in the sphingolipid profiles of irradiated cell extracts were demonstrated, confirming that lipidomic technologies are also useful tools for studying the key sphingolipid role in regulating cancer growth during radiotherapy.
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Affiliation(s)
- Martina Moggio
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (M.M.); (M.P.); (M.L.)
| | - Bahar Faramarzi
- Department of Mathematics and Physics, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy;
| | - Marianna Portaccio
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (M.M.); (M.P.); (M.L.)
| | - Lorenzo Manti
- Dipartimento di Fisica “E. Pancini”, Università Federico II di Napoli, 80126 Napoli, Italy;
- Istituto Nazionale di Fisica Nucleare (INFN), Sezione di Napoli, 80126 Napoli, Italy
| | - Maria Lepore
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (M.M.); (M.P.); (M.L.)
| | - Nadia Diano
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (M.M.); (M.P.); (M.L.)
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12
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Sharma D, Xuan Leong K, Palhares D, Czarnota GJ. Radiation combined with ultrasound and microbubbles: A potential novel strategy for cancer treatment. Z Med Phys 2023; 33:407-426. [PMID: 37586962 PMCID: PMC10517408 DOI: 10.1016/j.zemedi.2023.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/31/2023] [Accepted: 04/11/2023] [Indexed: 08/18/2023]
Abstract
Cancer is one of the leading causes of death worldwide. Several emerging technologies are helping to battle cancer. Cancer therapies have been effective at killing cancer cells, but a large portion of patients still die to this disease every year. As such, more aggressive treatments of primary cancers are employed and have been shown to be capable of saving a greater number of lives. Recent research advances the field of cancer therapy by employing the use of physical methods to alter tumor biology. It uses microbubbles to enhance radiation effect by damaging tumor vasculature followed by tumor cell death. The technique can specifically target tumor volumes by conforming ultrasound fields capable of microbubbles stimulation and localizing it to avoid vascular damage in surrounding tissues. Thus, this new application of ultrasound-stimulated microbubbles (USMB) can be utilized as a novel approach to cancer therapy by inducing vascular disruption resulting in tumor cell death. Using USMB alongside radiation has showed to augment the anti-vascular effect of radiation, resulting in enhanced tumor response. Recent work with nanobubbles has shown vascular permeation into intracellular space, extending the use of this new treatment method to potentially further improve the therapeutic effect of the ultrasound-based therapy. The significant enhancement of localized tumor cell kill means that radiation-based treatments can be made more potent with lower doses of radiation. This technique can manifest a greater impact on radiation oncology practice by increasing treatment effectiveness significantly while reducing normal tissue toxicity. This review article summarizes the past and recent advances in USMB enhancement of radiation treatments. The review mainly focuses on preclinical findings but also highlights some clinical findings that use USMB as a therapeutic modality in cancer therapy.
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Affiliation(s)
- Deepa Sharma
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Departments of Radiation Oncology, and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Kai Xuan Leong
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Daniel Palhares
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Departments of Radiation Oncology, and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Gregory J Czarnota
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada; Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Departments of Radiation Oncology, and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
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13
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Shi M, Tang C, Wu JX, Ji BW, Gong BM, Wu XH, Wang X. Mass Spectrometry Detects Sphingolipid Metabolites for Discovery of New Strategy for Cancer Therapy from the Aspect of Programmed Cell Death. Metabolites 2023; 13:867. [PMID: 37512574 PMCID: PMC10384871 DOI: 10.3390/metabo13070867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Sphingolipids, a type of bioactive lipid, play crucial roles within cells, serving as integral components of membranes and exhibiting strong signaling properties that have potential therapeutic implications in anti-cancer treatments. However, due to the diverse group of lipids and intricate mechanisms, sphingolipids still face challenges in enhancing the efficacy of different therapy approaches. In recent decades, mass spectrometry has made significant advancements in uncovering sphingolipid biomarkers and elucidating their impact on cancer development, progression, and resistance. Primary sphingolipids, such as ceramide and sphingosine-1-phosphate, exhibit contrasting roles in regulating cancer cell death and survival. The evasion of cell death is a characteristic hallmark of cancer cells, leading to treatment failure and a poor prognosis. The escape initiates with long-established apoptosis and extends to other programmed cell death (PCD) forms when patients experience chemotherapy, radiotherapy, and/or immunotherapy. Gradually, supportive evidence has uncovered the fundamental molecular mechanisms underlying various forms of PCD leading to the development of innovative molecular, genetic, and pharmacological tools that specifically target sphingolipid signaling nodes. In this study, we provide a comprehensive overview of the sphingolipid biomarkers revealed through mass spectrometry in recent decades, as well as an in-depth analysis of the six main forms of PCD (apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis) in aspects of tumorigenesis, metastasis, and tumor response to treatments. We review the corresponding small-molecule compounds associated with these processes and their potential implications in cancer therapy.
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Affiliation(s)
- Ming Shi
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Collaborative Innovation Center of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200438, China
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China
| | - Chao Tang
- National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jia-Xing Wu
- SINO-SWISS Institute of Advanced Technology, School of Microelectronics, Shanghai University, Shanghai 200444, China
| | - Bao-Wei Ji
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai 200032, China
| | - Bao-Ming Gong
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Collaborative Innovation Center of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200438, China
| | - Xiao-Hui Wu
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Collaborative Innovation Center of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200438, China
| | - Xue Wang
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Collaborative Innovation Center of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200438, China
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14
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Zhu H, Chen HJ, Wen HY, Wang ZG, Liu SL. Engineered Lipidic Nanomaterials Inspired by Sphingomyelin Metabolism for Cancer Therapy. Molecules 2023; 28:5366. [PMID: 37513239 PMCID: PMC10383197 DOI: 10.3390/molecules28145366] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/08/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Sphingomyelin (SM) and its metabolites are crucial regulators of tumor cell growth, differentiation, senescence, and programmed cell death. With the rise in lipid-based nanomaterials, engineered lipidic nanomaterials inspired by SM metabolism, corresponding lipid targeting, and signaling activation have made fascinating advances in cancer therapeutic processes. In this review, we first described the specific pathways of SM metabolism and the roles of their associated bioactive molecules in mediating cell survival or death. We next summarized the advantages and specific applications of SM metabolism-based lipidic nanomaterials in specific cancer therapies. Finally, we discussed the challenges and perspectives of this emerging and promising SM metabolism-based nanomaterials research area.
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Affiliation(s)
- Han Zhu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, China
| | - Hua-Jie Chen
- Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Hai-Yan Wen
- Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
| | - Zhi-Gang Wang
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, China
| | - Shu-Lin Liu
- State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Sciences, College of Chemistry, and School of Medicine, Nankai University, Tianjin 300071, China
- Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
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15
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Wilson GC, Patel SH, Wang J, Xu K, Turner KM, Becker KA, Carpinteiro A, Szabo I, Ahmad SA, Gulbins E. Acid sphingomyelinase expression is associated with survival in resectable pancreatic ductal adenocarcinoma. J Mol Med (Berl) 2023; 101:891-903. [PMID: 37246980 PMCID: PMC10300164 DOI: 10.1007/s00109-023-02331-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 04/04/2023] [Accepted: 05/03/2023] [Indexed: 05/30/2023]
Abstract
Pancreatic adenocarcinoma (PDAC) is one of the most common cancers worldwide. Unfortunately, the prognosis of PDAC is rather poor, and for instance, in the USA, over 47,000 people die because of pancreatic cancer annually. Here, we demonstrate that high expression of acid sphingomyelinase in PDAC strongly correlates with long-term survival of patients, as revealed by the analysis of two independent data sources. The positive effects of acid sphingomyelinase expression on long-term survival of PDAC patients were independent of patient demographics as well as tumor grade, lymph node involvement, perineural invasion, tumor stage, lymphovascular invasion, and adjuvant therapy. We also demonstrate that genetic deficiency or pharmacological inhibition of the acid sphingomyelinase promotes tumor growth in an orthotopic mouse model of PDAC. This is mirrored by a poorer pathologic response, as defined by the College of American Pathologists (CAP) score for pancreatic cancer, to neoadjuvant therapy of patients co-treated with functional inhibitors of the acid sphingomyelinase, in particular tricyclic antidepressants and selective serotonin reuptake inhibitors, in a retrospective analysis. Our data indicate expression of the acid sphingomyelinase in PDAC as a prognostic marker for tumor progression. They further suggest that the use of functional inhibitors of the acid sphingomyelinase, at least of tricyclic antidepressants and selective serotonin reuptake inhibitors in patients with PDAC, is contra-indicated. Finally, our data also suggest a potential novel treatment of PDAC patients with recombinant acid sphingomyelinase. KEY MESSAGES: Pancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis. Expression of acid sphingomyelinase (ASM) determines outcome of PDAC. Genetic deficiency or pharmacologic inhibition of ASM promotes tumor growth in a mouse model. Inhibition of ASM during neoadjuvant treatment for PDAC correlates with worse pathology. ASM expression is a prognostic marker and potential target in PDAC.
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Affiliation(s)
- Gregory C Wilson
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 05, Cincinnati, OH, 45267-0558, USA.
| | - Sameer H Patel
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 05, Cincinnati, OH, 45267-0558, USA
| | - Jiang Wang
- Departments of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Kui Xu
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 05, Cincinnati, OH, 45267-0558, USA
| | - Kevin M Turner
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 05, Cincinnati, OH, 45267-0558, USA
| | - Katrin Anne Becker
- Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Alexander Carpinteiro
- Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Ildiko Szabo
- Department of Biology and CNR Institute of Neurosciences, University of Padua, Padua, Italy
| | - Syed A Ahmad
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 05, Cincinnati, OH, 45267-0558, USA
| | - Erich Gulbins
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML 05, Cincinnati, OH, 45267-0558, USA.
- Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
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16
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Pfrieger FW. The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism. Prog Lipid Res 2023; 90:101225. [PMID: 37003582 DOI: 10.1016/j.plipres.2023.101225] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/27/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023]
Abstract
Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.
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17
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Sharma GP, Himburg HA. Organ-Specific Endothelial Dysfunction Following Total Body Irradiation Exposure. TOXICS 2022; 10:toxics10120747. [PMID: 36548580 PMCID: PMC9781710 DOI: 10.3390/toxics10120747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/28/2022] [Accepted: 11/30/2022] [Indexed: 05/14/2023]
Abstract
As the single cell lining of the heart and all blood vessels, the vascular endothelium serves a critical role in maintaining homeostasis via control of vascular tone, immune cell recruitment, and macromolecular transit. For victims of acute high-dose radiation exposure, damage to the vascular endothelium may exacerbate the pathogenesis of acute and delayed multi-organ radiation toxicities. While commonalities exist between radiation-induced endothelial dysfunction in radiosensitive organs, the vascular endothelium is known to be highly heterogeneous as it is required to serve tissue and organ specific roles. In keeping with its organ and tissue specific functionality, the molecular and cellular response of the endothelium to radiation injury varies by organ. Therefore, in the development of medical countermeasures for multi-organ injury, it is necessary to consider organ and tissue-specific endothelial responses to both injury and candidate mitigators. The purpose of this review is to summarize the pathogenesis of endothelial dysfunction following total or near total body irradiation exposure at the level of individual radiosensitive organs.
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Affiliation(s)
- Guru Prasad Sharma
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Heather A. Himburg
- Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Correspondence: ; Tel.: +1-(414)-955-4676
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18
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Pal P, Atilla-Gokcumen GE, Frasor J. Emerging Roles of Ceramides in Breast Cancer Biology and Therapy. Int J Mol Sci 2022; 23:ijms231911178. [PMID: 36232480 PMCID: PMC9569866 DOI: 10.3390/ijms231911178] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy.
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Affiliation(s)
- Purab Pal
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - G. Ekin Atilla-Gokcumen
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, NY 14260, USA
- Correspondence: (G.E.A.-G.); (J.F.)
| | - Jonna Frasor
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
- Correspondence: (G.E.A.-G.); (J.F.)
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19
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Berg AL, Rowson-Hodel A, Wheeler MR, Hu M, Free SR, Carraway KL. Engaging the Lysosome and Lysosome-Dependent Cell Death in Cancer. Breast Cancer 2022. [DOI: 10.36255/exon-publications-breast-cancer-lysosome] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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20
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Mostaghimi S, Mehrvar S, Foomani FH, Narayanan J, Fish B, Camara AKS, Medhora M, Ranji M. Vascular regression in the kidney: changes in 3D vessel structure with time post-irradiation. BIOMEDICAL OPTICS EXPRESS 2022; 13:4338-4352. [PMID: 36032582 PMCID: PMC9408260 DOI: 10.1364/boe.464426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 07/02/2022] [Accepted: 07/11/2022] [Indexed: 06/15/2023]
Abstract
Though angiogenesis has been investigated in depth, vascular regression and rarefaction remain poorly understood. Regression of renal vasculature accompanies many pathological states such as diabetes, hypertension, atherosclerosis, and radiotherapy. Radiation decreases microvessel density in multiple organs, though the mechanism is not known. By using a whole animal (rat) model with a single dose of partial body irradiation to the kidney, changes in the volume of renal vasculature were recorded at two time points, 60 and 90 days after exposure. Next, a novel vascular and metabolic imaging (VMI) technique was used to computationally assess 3D vessel diameter, volume, branch depth, and density over multiple levels of branching down to 70 µm. Four groups of rats were studied, of which two groups received a single dose of 12.5 Gy X-rays. The kidneys were harvested after 60 or 90 days from one irradiated and one non-irradiated group at each time point. Measurements of the 3D vasculature showed that by day-90 post-radiation, when renal function is known to deteriorate, total vessel volume, vessel density, maximum branch depth, and the number of terminal points in the kidneys decreased by 55%, 57%, 28%, and 53%, respectively. Decreases in the same parameters were not statistically significant at 60 days post-irradiation. Smaller vessels with internal diameters of 70-450 µm as well as large vessels of diameter 451-850 µm, both decreased by 90 days post-radiation. Vascular regression in the lungs of the same strain of irradiated rats has been reported to occur before 60 days supporting the hypothesis that this process is regulated in an organ-specific manner and occurs by a concurrent decrease in luminal diameters of small as well as large blood vessels.
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Affiliation(s)
- Soudeh Mostaghimi
- Department of Biomedical Engineering at University of California, Irvine, CA 92697, USA
| | | | - Farnaz H. Foomani
- Department of Electrical Engineering and Computer Science at University of Wisconsin, Milwaukee, WI 53211, USA
| | - Jayashree Narayanan
- Department of Radiation Oncology and Cardiovascular Research Center at Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Brian Fish
- Department of Radiation Oncology and Cardiovascular Research Center at Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Amadou K. S. Camara
- Department of Anesthesiology and Cardiovascular Research Center at Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Meetha Medhora
- Department of Radiation Oncology and Cardiovascular Research Center at Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Contributed equally
| | - Mahsa Ranji
- Department of Electrical Engineering and Computer Science at Florida Atlantic University, Boca Raton, FL 33431, USA
- Contributed equally
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21
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Sharma D, Czarnota GJ. Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy. Int J Mol Sci 2022; 23:ijms23126671. [PMID: 35743121 PMCID: PMC9223569 DOI: 10.3390/ijms23126671] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/31/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
Sphingolipids are well-recognized critical components in several biological processes. Ceramides constitute a class of sphingolipid metabolites that are involved in important signal transduction pathways that play key roles in determining the fate of cells to survive or die. Ceramide accumulated in cells causes apoptosis; however, ceramide metabolized to sphingosine promotes cell survival and angiogenesis. Studies suggest that vascular-targeted therapies increase endothelial cell ceramide resulting in apoptosis that leads to tumour cure. Specifically, ultrasound-stimulated microbubbles (USMB) used as vascular disrupting agents can perturb endothelial cells, eliciting acid sphingomyelinase (ASMase) activation accompanied by ceramide release. This phenomenon results in endothelial cell death and vascular collapse and is synergistic with other antitumour treatments such as radiation. In contrast, blocking the generation of ceramide using multiple approaches, including the conversion of ceramide to sphingosine-1-phosphate (S1P), abrogates this process. The ceramide-based cell survival "rheostat" between these opposing signalling metabolites is essential in the mechanotransductive vascular targeting following USMB treatment. In this review, we aim to summarize the past and latest findings on ceramide-based vascular-targeted strategies, including novel mechanotransductive methodologies.
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Affiliation(s)
- Deepa Sharma
- Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, ON M4N 3M5, Canada
- Correspondence: ; Tel.: +1-416-480-6100 (ext. 89533)
| | - Gregory J. Czarnota
- Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, ON M4N 3M5, Canada
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22
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Gamma Irradiation Triggers Immune Escape in Glioma-Propagating Cells. Cancers (Basel) 2022; 14:cancers14112728. [PMID: 35681710 PMCID: PMC9179833 DOI: 10.3390/cancers14112728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/13/2022] [Accepted: 05/18/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Stem cell-like glioma-propagating cells (GPCs) are crucial for initiation, growth, and treatment resistance of glioblastoma multiforme. Due to their strong immunosuppressive activities, they essentially limit immunotherapeutic approaches. This study offers a new model of radio-selected patient-derived GPCs mimicking a clinical treatment regime of tumor irradiation which is especially useful for immunotherapeutic studies. We provide evidence that clinically relevant, sub-lethal fractions of γ radiation select for a more radio-resistant GPC phenotype with lower immunogenic potential, potentially hampering the success of adjuvant T-cell-based immunotherapies. The immune evasion in GPCs was characterized by quantitative proteomics. It revealed a marked downregulation of the antigen processing machinery in lipid rafts of these cells, leading to reduced MHC surface expression and weaker cytotoxic T lymphocyte (CTL) recognition. Abstract Glioblastoma multiforme is the most common and devastating form of brain tumor for which only palliative radio- and chemotherapy exists. Although some clinical studies on vaccination approaches have shown promising efficacy due to their potential to generate long-term immune surveillance against cancer cells, the evasion mechanisms preventing therapy response are largely uncharacterized. Here, we studied the response of glioblastoma-propagating cells (GPCs) to clinically relevant doses of γ radiation. GPCs were treated with 2.5 Gy of γ radiation in seven consecutive cellular passages to select for GPCs with increased colony-forming properties and intrinsic or radiation-induced resistance (rsGPCs). Quantitative proteomic analysis of the cellular signaling platforms of the detergent-resistant membranes (lipid rafts) in GPCs vs. rsGPCs revealed a downregulation of the MHC class I antigen-processing and -presentation machinery. Importantly, the radio-selected GPCs showed reduced susceptibility towards cytotoxic CD8+ T-cell-mediated killing. While previous studies suggested that high-dose irradiation results in enhanced antigen presentation, we demonstrated that clinically relevant sub-lethal fractionated irradiation results in reduced expression of components of the MHC class I antigen-processing and -presentation pathway leading to immune escape.
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Fujita J, Taniguchi M, Hashizume C, Ueda Y, Sakai S, Kondo T, Hashimoto-Nishimura M, Hanada K, Kosaka T, Okazaki T. Nuclear Ceramide Is Associated with Ataxia Telangiectasia Mutated Activation in the Neocarzinostatin-Induced Apoptosis of Lymphoblastoid Cells. Mol Pharmacol 2022; 101:322-333. [PMID: 35273080 DOI: 10.1124/molpharm.121.000379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 02/22/2022] [Indexed: 01/14/2023] Open
Abstract
Ceramide is a bioactive sphingolipid that mediates ionizing radiation- and chemotherapy-induced apoptosis. Neocarzinostatin (NCS) is a genotoxic anti-cancer drug that induces apoptosis in response to DNA double-strand breaks (DSBs) through ataxia telangiectasia mutated (ATM) activation. However, the involvement of ceramide in NCS-evoked nuclear events such as DSB-activated ATM has not been clarified. Here, we found that nuclear ceramide increased by NCS-mediated apoptosis through the enhanced assembly of ATM and the meiotic recombination 11/double-strand break repair/Nijmengen breakage syndrome 1 (MRN) complex proteins in human lymphoblastoid L-39 cells. NCS induced an increase of ceramide production through activation of neutral sphingomyelinase (nSMase) and suppression of sphingomyelin synthase (SMS) upstream of DSB-mediated ATM activation. In ATM-deficient lymphoblastoid AT-59 cells compared with L-39 cells, NCS treatment showed a decrease of apoptosis even though ceramide increase and DSBs were observed. Expression of wild-type ATM, but not the kinase-dead mutant ATM, in AT-59 cells increased NCS-induced apoptosis despite similar ceramide accumulation. Interestingly, NCS increased ceramide content in the nucleus through nSMase activation and SMS suppression and promoted colocalization of ceramide with phosphorylated ATM and foci of MRN complex. Inhibition of ceramide generation by the overexpression of SMS suppressed NCS-induced apoptosis through the inhibition of ATM activation and assembly of the MRN complex. In addition, inhibition of ceramide increased by the nSMase inhibitor GW4869 prevented NCS-mediated activation of the ATM. Therefore, our findings suggest the involvement of the nuclear ceramide with ATM activation in NCS-mediated apoptosis. SIGNIFICANCE STATEMENT: This study demonstrates that regulation of ceramide with neutral sphingomyelinase and sphingomyelin synthase in the nucleus in double-strand break-mimetic agent neocarzinostatin (NCS)-induced apoptosis. This study also showed that ceramide increase in the nucleus plays a role in NCS-induced apoptosis through activation of the ataxia telangiectasia mutated/meiotic recombination 11/double-strand break repair/Nijmengen breakage syndrome 1 complex in human lymphoblastoid cells.
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Affiliation(s)
- Jun Fujita
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
| | - Makoto Taniguchi
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
| | - Chieko Hashizume
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
| | - Yoshibumi Ueda
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
| | - Shota Sakai
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
| | - Tadakazu Kondo
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
| | - Mayumi Hashimoto-Nishimura
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
| | - Kentaro Hanada
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
| | - Takeo Kosaka
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
| | - Toshiro Okazaki
- Division of General and Digestive Surgery, Department of Medicine (J.F., C.H., T.K.) and Medical Research Institute (M.T.), Kanazawa Medical University, Ishikawa, Japan; Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Ishikawa, Japan (C.H., T.O.); Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan (Y.U.); Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan. (S.S., K.H.); Department of Hematology/Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan (T.K.); and Department of Hematology/Oncology, Faculty of Medicine, Tottori University, Yonago, Japan (M.H.-N.)
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Application of Ultrasound Combined with Microbubbles for Cancer Therapy. Int J Mol Sci 2022; 23:ijms23084393. [PMID: 35457210 PMCID: PMC9026557 DOI: 10.3390/ijms23084393] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 02/07/2023] Open
Abstract
At present, cancer is one of the leading causes of death worldwide. Treatment failure remains one of the prime hurdles in cancer treatment due to the metastatic nature of cancer. Techniques have been developed to hinder the growth of tumours or at least to stop the metastasis process. In recent years, ultrasound therapy combined with microbubbles has gained immense success in cancer treatment. Ultrasound-stimulated microbubbles (USMB) combined with other cancer treatments including radiation therapy, chemotherapy or immunotherapy has demonstrated potential improved outcomes in various in vitro and in vivo studies. Studies have shown that low dose radiation administered with USMB can have similar effects as high dose radiation therapy. In addition, the use of USMB in conjunction with radiotherapy or chemotherapy can minimize the toxicity of high dose radiation or chemotherapeutic drugs, respectively. In this review, we discuss the biophysical properties of USMB treatment and its applicability in cancer therapy. In particular, we highlight important preclinical and early clinical findings that demonstrate the antitumour effect combining USMB and other cancer treatment modalities (radiotherapy and chemotherapy). Our review mainly focuses on the tumour vascular effects mediated by USMB and these cancer therapies. We also discuss several current limitations, in addition to ongoing and future efforts for applying USMB in cancer treatment.
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Favaudon V, Labarbe R, Limoli CL. Model studies of the role of oxygen in the FLASH effect. Med Phys 2022; 49:2068-2081. [PMID: 34407219 PMCID: PMC8854455 DOI: 10.1002/mp.15129] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 06/02/2021] [Accepted: 06/10/2021] [Indexed: 12/13/2022] Open
Abstract
Current radiotherapy facilities are standardized to deliver dose rates around 0.1-0.4 Gy/s in 2 Gy daily fractions, designed to deliver total accumulated doses to reach the tolerance limit of normal tissues undergoing irradiation. FLASH radiotherapy (FLASH-RT), on the other hand, relies on facilities capable of delivering ultrahigh dose rates in large doses in a single microsecond pulse, or in a few pulses given over a very short time sequence. For example, most studies to date have implemented 4-6 MeV electrons with intra-pulse dose rates in the range 106 -107 Gy/s. The proposed dependence of the FLASH effect on oxygen tension has stimulated several theoretical models based on three different hypotheses: (i) Radiation-induced transient oxygen depletion; (ii) cell-specific differences in the ability to detoxify and/or recover from injury caused by reactive oxygen species; (iii) self-annihilation of radicals by bimolecular recombination. This article focuses on the observations supporting or refuting these models in the frame of the chemical-biological bases of the impact of oxygen on the radiation response of cell free, in vitro and in vivo model systems.
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Affiliation(s)
- Vincent Favaudon
- Institut Curie, Inserm U 1021- CNRS UMR 3347, University Paris-Saclay, PSL Research University, Centre Universitaire, 91405 Orsay Cedex, France
- Corresponding author:
| | - Rudi Labarbe
- Ion Beam Applications S.A. (IBA), Louvain-la-Neuve, Belgium
| | - Charles L. Limoli
- Dept. of Radiation Oncology, Medical Sciences I, B146B, Irvine, California 92697-2695, USA
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Read GH, Bailleul J, Vlashi E, Kesarwala AH. Metabolic response to radiation therapy in cancer. Mol Carcinog 2022; 61:200-224. [PMID: 34961986 PMCID: PMC10187995 DOI: 10.1002/mc.23379] [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: 08/11/2021] [Revised: 12/01/2021] [Accepted: 12/01/2021] [Indexed: 11/11/2022]
Abstract
Tumor metabolism has emerged as a hallmark of cancer and is involved in carcinogenesis and tumor growth. Reprogramming of tumor metabolism is necessary for cancer cells to sustain high proliferation rates and enhanced demands for nutrients. Recent studies suggest that metabolic plasticity in cancer cells can decrease the efficacy of anticancer therapies by enhancing antioxidant defenses and DNA repair mechanisms. Studying radiation-induced metabolic changes will lead to a better understanding of radiation response mechanisms as well as the identification of new therapeutic targets, but there are few robust studies characterizing the metabolic changes induced by radiation therapy in cancer. In this review, we will highlight studies that provide information on the metabolic changes induced by radiation and oxidative stress in cancer cells and the associated underlying mechanisms.
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Affiliation(s)
- Graham H. Read
- Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Justine Bailleul
- Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Erina Vlashi
- Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California
| | - Aparna H. Kesarwala
- Department of Radiation Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
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Bataller M, Sánchez-García A, Garcia-Mayea Y, Mir C, Rodriguez I, LLeonart ME. The Role of Sphingolipids Metabolism in Cancer Drug Resistance. Front Oncol 2022; 11:807636. [PMID: 35004331 PMCID: PMC8733468 DOI: 10.3389/fonc.2021.807636] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/07/2021] [Indexed: 12/25/2022] Open
Abstract
Drug resistance continues to be one of the major challenges to cure cancer. As research in this field evolves, it has been proposed that numerous bioactive molecules might be involved in the resistance of cancer cells to certain chemotherapeutics. One well-known group of lipids that play a major role in drug resistance are the sphingolipids. Sphingolipids are essential components of the lipid raft domains of the plasma membrane and this structural function is important for apoptosis and/or cell proliferation. Dysregulation of sphingolipids, including ceramide, sphingomyelin or sphingosine 1-phosphate, has been linked to drug resistance in different types of cancer, including breast, melanoma or colon cancer. Sphingolipid metabolism is complex, involving several lipid catabolism with the participation of key enzymes such as glucosylceramide synthase (GCS) and sphingosine kinase 1 (SPHK1). With an overview of the latest available data on this topic and its implications in cancer therapy, this review focuses on the main enzymes implicated in sphingolipids metabolism and their intermediate metabolites involved in cancer drug resistance.
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Affiliation(s)
- Marina Bataller
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain
| | - Almudena Sánchez-García
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain
| | - Yoelsis Garcia-Mayea
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain
| | - Cristina Mir
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain
| | - Isabel Rodriguez
- Assistant Director of Nursing, Nursing Management Service Hospital Vall d'Hebron, Barcelona, Spain
| | - Matilde Esther LLeonart
- Biomedical Research in Cancer Stem Cells Group, Vall d´Hebron Research Institute (VHIR), Barcelona, Spain.,Spanish Biomedical Research Network Centre in Oncology, CIBERONC, Madrid, Spain
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28
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Hose M, Günther A, Naser E, Schumacher F, Schönberger T, Falkenstein J, Papadamakis A, Kleuser B, Becker KA, Gulbins E, Haimovitz-Friedman A, Buer J, Westendorf AM, Hansen W. Cell-intrinsic ceramides determine T cell function during melanoma progression. eLife 2022; 11:83073. [PMID: 36426850 PMCID: PMC9699697 DOI: 10.7554/elife.83073] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/15/2022] [Indexed: 11/27/2022] Open
Abstract
Acid sphingomyelinase (Asm) and acid ceramidase (Ac) are parts of the sphingolipid metabolism. Asm hydrolyzes sphingomyelin to ceramide, which is further metabolized to sphingosine by Ac. Ceramide generates ceramide-enriched platforms that are involved in receptor clustering within cellular membranes. However, the impact of cell-intrinsic ceramide on T cell function is not well characterized. By using T cell-specific Asm- or Ac-deficient mice, with reduced or elevated ceramide levels in T cells, we identified ceramide to play a crucial role in T cell function in vitro and in vivo. T cell-specific ablation of Asm in Smpd1fl/fl/Cd4cre/+ (Asm/CD4cre) mice resulted in enhanced tumor progression associated with impaired T cell responses, whereas Asah1fl/fl/Cd4cre/+ (Ac/CD4cre) mice showed reduced tumor growth rates and elevated T cell activation compared to the respective controls upon tumor transplantation. Further in vitro analysis revealed that decreased ceramide content supports CD4+ regulatory T cell differentiation and interferes with cytotoxic activity of CD8+ T cells. In contrast, elevated ceramide concentration in CD8+ T cells from Ac/CD4cre mice was associated with enhanced cytotoxic activity. Strikingly, ceramide co-localized with the T cell receptor (TCR) and CD3 in the membrane of stimulated T cells and phosphorylation of TCR signaling molecules was elevated in Ac-deficient T cells. Hence, our results indicate that modulation of ceramide levels, by interfering with the Asm or Ac activity has an effect on T cell differentiation and function and might therefore represent a novel therapeutic strategy for the treatment of T cell-dependent diseases such as tumorigenesis.
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Affiliation(s)
- Matthias Hose
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | - Anne Günther
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | - Eyad Naser
- Institute of Molecular Biology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | | | - Tina Schönberger
- Institute of Physiology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | - Julia Falkenstein
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | - Athanasios Papadamakis
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | | | - Katrin Anne Becker
- Institute of Molecular Biology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | - Erich Gulbins
- Institute of Molecular Biology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | | | - Jan Buer
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | - Astrid M Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-EssenEssenGermany
| | - Wiebke Hansen
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-EssenEssenGermany
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29
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Radiobiology of Targeted Alpha Therapy. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00093-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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30
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Lee CL, Wright AO, Lee JW, Brownstein J, Hasapis S, Satow S, Da Silva Campos L, Williams N, Ma Y, Luo L, Johnson T, Daniel AR, Harrison WT, Oldham M, Kirsch DG. Sensitization of Endothelial Cells to Ionizing Radiation Exacerbates Delayed Radiation Myelopathy in Mice. Radiat Res 2021; 197:0. [PMID: 34724704 DOI: 10.1667/rade-21-00166.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 09/23/2021] [Indexed: 11/03/2022]
Abstract
Delayed radiation myelopathy is a rare, but significant late side effect from radiation therapy that can lead to paralysis. The cellular and molecular mechanisms leading to delayed radiation myelopathy are not completely understood but may be a consequence of damage to oligodendrocyte progenitor cells and vascular endothelial cells. Here, we aimed to determine the contribution of endothelial cell damage to the development of radiation-induced spinal cord injury using a genetically defined mouse model in which endothelial cells are sensitized to radiation due to loss of the tumor suppressor p53. Tie2Cre; p53FL/+ and Tie2Cre; p53FL/- mice, which lack one and both alleles of p53 in endothelial cells, respectively, were treated with focal irradiation that specifically targeted the lumbosacral region of the spinal cord. The development of hindlimb paralysis was followed for up to 18 weeks after either a 26.7 Gy or 28.4 Gy dose of radiation. During 18 weeks of follow-up, 83% and 100% of Tie2Cre; p53FL/- mice developed hindlimb paralysis after 26.7 and 28.4 Gy, respectively. In contrast, during this period only 8% of Tie2Cre; p53FL/+ mice exhibited paralysis after 28.4 Gy. In addition, 8 weeks after 28.4 Gy the irradiated spinal cord from Tie2Cre; p53FL/- mice showed a significantly higher fractional area positive for the neurological injury marker glial fibrillary acidic protein (GFAP) compared with the irradiated spinal cord from Tie2Cre; p53FL/+ mice. Together, our findings show that deletion of p53 in endothelial cells sensitizes mice to the development of delayed radiation myelopathy indicating that endothelial cells are a critical cellular target of radiation that regulates myelopathy.
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Affiliation(s)
- Chang-Lung Lee
- Department of Radiation Oncology.,Department of Pathology
| | | | | | | | | | | | | | | | - Yan Ma
- Department of Radiation Oncology
| | | | | | | | - William T Harrison
- Department of Pathology, Wake Forest Baptist Health, Winston Salem, North Carolina 27157
| | | | - David G Kirsch
- Department of Radiation Oncology.,Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710
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Li S, An W, Wang B, Li J, Qu Y, Zhang H, Zhang Y, Wang S, Qin L. Inorganic nitrate alleviates irradiation-induced salivary gland damage by inhibiting pyroptosis. Free Radic Biol Med 2021; 175:130-140. [PMID: 34454049 DOI: 10.1016/j.freeradbiomed.2021.08.227] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 08/11/2021] [Accepted: 08/24/2021] [Indexed: 01/02/2023]
Abstract
Over 80% of patients undergoing radiotherapy (RT) for head and neck cancer (HNC) suffer reduced saliva secretion and dry mouth symptoms due to salivary gland damage. Although therapeutic interventions to alleviate such RT-induced damage are available, long-term hypofunction remains a significant issue. Therefore, novel therapeutic solutions to prevent irradiation (IR)-induced salivary gland damage are required. This study explored the protective effect of inorganic nitrate in preventing IR-induced salivary gland injury via pyroptosis suppression, both in vivo and in vitro. In the treatment group, C57BL/6 mice were pretreated with 2 mmol/L NaNO3 supplied in drinking water one week before a single-dose of 15 Gy IR in the submandibular gland (SMG) region. Human vein endothelial cells (HUVECs) and mice SMG cells were treated with 10 μmol/L or 100 μmol/L NaNO3 2 h before a single-dose of 8 Gy IR. In vivo, IR-induced decreased saliva flow rate and body weight loss could be alleviated by nitrate supplementation. Nitrate prevented acinar and microvascular endothelial cell loss. Moreover, nitrate improved mitochondrial function and significantly decreased pyroptosis-related indexes. In vitro, nitrate supplementation reduced reactive oxygen species (ROS) generation by preserving mitochondrial homeostasis to inhibit NLPR3 inflammasome-mediated pyroptosis both in HUVECs and SMG cells. Nitrate showed potential as an oral protective agent to prevent IR-induced salivary gland damage; prospective insight into the underlying molecular mechanisms is presented.
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Affiliation(s)
- Shaoqing Li
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China; Beijing Laboratory of Oral Helath, Capital Medical University, Beijing 100069, China; Department of Stomatology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Wei An
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China; Beijing Laboratory of Oral Helath, Capital Medical University, Beijing 100069, China; Department of Oral and Maxillofacial Surgery, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, 030012, China
| | - Bin Wang
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Jing Li
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Yi Qu
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Haoyang Zhang
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Yingrui Zhang
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China
| | - Songlin Wang
- Beijing Laboratory of Oral Helath, Capital Medical University, Beijing 100069, China; Department of Biochemistry and Molecular Biology, Capital Medical University School of Basic Medicine, Beijing 100069, China.
| | - Lizheng Qin
- Department of Oral and Maxillofacial & Head and Neck Oncology, Beijing Stomatological Hospital, Capital Medical University, Beijing, 100050, China; Beijing Laboratory of Oral Helath, Capital Medical University, Beijing 100069, China.
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32
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Lee H, Choi SQ. Sphingomyelinase-Mediated Multitimescale Clustering of Ganglioside GM1 in Heterogeneous Lipid Membranes. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2101766. [PMID: 34473415 PMCID: PMC8529493 DOI: 10.1002/advs.202101766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/19/2021] [Indexed: 05/05/2023]
Abstract
Several signaling processes in the plasma membrane are intensified by ceramides that are formed by sphingomyelinase-mediated hydrolysis of sphingomyelin. These ceramides trigger clustering of signaling-related biomolecules, but how they concentrate such biomolecules remains unclear. Here, the spatiotemporal localization of ganglioside GM1, a glycolipid receptor involved in signaling, during sphingomyelinase-mediated hydrolysis is described. Real-time visualization of the dynamic remodeling of the heterogeneous lipid membrane that occurs due to sphingomyelinase action is used to examine GM1 clustering, and unexpectedly, it is found that it is more complex than previously thought. Specifically, lipid membranes generate two distinct types of condensed GM1: 1) rapidly formed but short-lived GM1 clusters that are formed in ceramide-rich domains nucleated from the liquid-disordered phase; and 2) late-onset yet long-lasting, high-density GM1 clusters that are formed in the liquid-ordered phase. These findings suggest that multiple pathways exist in a plasma membrane to synergistically facilitate the rapid amplification and persistence of signals.
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Affiliation(s)
- Hyun‐Ro Lee
- Department of Chemical and Biomolecular EngineeringKorea Advanced Institute of Science and Technology (KAIST)Daejeon34141Republic of Korea
| | - Siyoung Q. Choi
- Department of Chemical and Biomolecular EngineeringKorea Advanced Institute of Science and Technology (KAIST)Daejeon34141Republic of Korea
- KAIST Institute for the NanoCenturyKorea Advanced Institute of Science and Technology (KAIST)Daejeon34141Republic of Korea
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Acid sphingomyelinase promotes SGK1-dependent vascular calcification. Clin Sci (Lond) 2021; 135:515-534. [PMID: 33479769 PMCID: PMC7859357 DOI: 10.1042/cs20201122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 01/07/2021] [Accepted: 01/21/2021] [Indexed: 12/20/2022]
Abstract
In chronic kidney disease (CKD), hyperphosphatemia is a key factor promoting medial vascular calcification, a common complication associated with cardiovascular events and high mortality. Vascular calcification involves osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), but the complex signaling events inducing pro-calcific pathways are incompletely understood. The present study investigated the role of acid sphingomyelinase (ASM)/ceramide as regulator of VSMC calcification. In vitro, both, bacterial sphingomyelinase and phosphate increased ceramide levels in VSMCs. Bacterial sphingomyelinase as well as ceramide supplementation stimulated osteo-/chondrogenic transdifferentiation during control and high phosphate conditions and augmented phosphate-induced calcification of VSMCs. Silencing of serum- and glucocorticoid-inducible kinase 1 (SGK1) blunted the pro-calcific effects of bacterial sphingomyelinase or ceramide. Asm deficiency blunted vascular calcification in a cholecalciferol-overload mouse model and ex vivo isolated-perfused arteries. In addition, Asm deficiency suppressed phosphate-induced osteo-/chondrogenic signaling and calcification of cultured VSMCs. Treatment with the functional ASM inhibitors amitriptyline or fendiline strongly blunted pro-calcific signaling pathways in vitro and in vivo. In conclusion, ASM/ceramide is a critical upstream regulator of vascular calcification, at least partly, through SGK1-dependent signaling. Thus, ASM inhibition by repurposing functional ASM inhibitors to reduce the progression of vascular calcification during CKD warrants further study.
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Jacobson JR. Sphingolipids as a Novel Therapeutic Target in Radiation-Induced Lung Injury. Cell Biochem Biophys 2021; 79:509-516. [PMID: 34370281 PMCID: PMC8551086 DOI: 10.1007/s12013-021-01022-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 07/08/2021] [Indexed: 12/25/2022]
Abstract
Radiation-induced lung injury (RILI) is a potential complication of thoracic radiotherapy that can result in pneumonitis or pulmonary fibrosis and is associated with significant morbidity and mortality. The pathobiology of RILI is complex and includes the generation of free radicals and DNA damage that precipitate oxidative stress, endothelial cell (EC), and epithelial cell injury and inflammation. While the cellular events involved continue to be elucidated and characterized, targeted and effective therapies for RILI remain elusive. Sphingolipids are known to mediate EC function including many of the cell signaling events associated with the elaboration of RILI. Sphingosine-1-phosphate (S1P) and S1P analogs enhance EC barrier function in vitro and have demonstrated significant protective effects in vivo in a variety of acute lung injury models including RILI. Similarly, statin drugs that have pleiotropic effects that include upregulation of EC S1P receptor 1 (S1PR1) have been found to be strongly protective in a small animal RILI model. Thus, targeting of EC sphingosine signaling, either directly or indirectly, to augment EC function and thereby attenuate EC permeability and inflammatory responses, represents a novel and promising therapeutic strategy for the prevention or treatment of RILI.
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Affiliation(s)
- Jeffrey R Jacobson
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, USA.
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35
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Krones D, Rühling M, Becker KA, Kunz TC, Sehl C, Paprotka K, Gulbins E, Fraunholz M. Staphylococcus aureus α-Toxin Induces Acid Sphingomyelinase Release From a Human Endothelial Cell Line. Front Microbiol 2021; 12:694489. [PMID: 34394034 PMCID: PMC8358437 DOI: 10.3389/fmicb.2021.694489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/05/2021] [Indexed: 11/14/2022] Open
Abstract
Staphylococcus aureus (S. aureus) is well known to express a plethora of toxins of which the pore-forming hemolysin A (α-toxin) is the best-studied cytolysin. Pore-forming toxins (PFT) permeabilize host membranes during infection thereby causing concentration-dependent effects in host cell membranes ranging from disordered ion fluxes to cytolysis. Host cells possess defense mechanisms against PFT attack, resulting in endocytosis of the breached membrane area and delivery of repair vesicles to the insulted plasma membrane as well as a concurrent release of membrane repair enzymes. Since PFTs from several pathogens have been shown to recruit membrane repair components, we here investigated whether staphylococcal α-toxin is able to induce these mechanisms in endothelial cells. We show that S. aureus α-toxin induced increase in cytosolic Ca2+ in endothelial cells, which was accompanied by p38 MAPK phosphorylation. Toxin challenge led to increased endocytosis of an extracellular fluid phase marker as well as increased externalization of LAMP1-positive membranes suggesting that peripheral lysosomes are recruited to the insulted plasma membrane. We further observed that thereby the lysosomal protein acid sphingomyelinase (ASM) was released into the cell culture medium. Thus, our results show that staphylococcal α-toxin triggers mechanisms in endothelial cells, which have been implicated in membrane repair after damage of other cell types by different toxins.
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Affiliation(s)
- David Krones
- Chair of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany
| | - Marcel Rühling
- Chair of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany
| | - Katrin Anne Becker
- Institute of Molecular Biology, University of Duisburg-Essen, University Hospital, Essen, Germany
| | - Tobias C Kunz
- Chair of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany
| | - Carolin Sehl
- Institute of Molecular Biology, University of Duisburg-Essen, University Hospital, Essen, Germany
| | - Kerstin Paprotka
- Chair of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany
| | - Erich Gulbins
- Institute of Molecular Biology, University of Duisburg-Essen, University Hospital, Essen, Germany.,Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Martin Fraunholz
- Chair of Microbiology, Biocenter, University of Würzburg, Würzburg, Germany
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36
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Pouget JP, Constanzo J. Revisiting the Radiobiology of Targeted Alpha Therapy. Front Med (Lausanne) 2021; 8:692436. [PMID: 34386508 PMCID: PMC8353448 DOI: 10.3389/fmed.2021.692436] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022] Open
Abstract
Targeted alpha therapy (TAT) using alpha particle-emitting radionuclides is in the spotlight after the approval of 223RaCl2 for patients with metastatic castration-resistant prostate cancer and the development of several alpha emitter-based radiopharmaceuticals. It is acknowledged that alpha particles are highly cytotoxic because they produce complex DNA lesions. Hence, the nucleus is considered their critical target, and many studies did not report any effect in other subcellular compartments. Moreover, their physical features, including their range in tissues (<100 μm) and their linear energy transfer (50–230 keV/μm), are well-characterized. Theoretically, TAT is indicated for very small-volume, disseminated tumors (e.g., micrometastases, circulating tumor cells). Moreover, due to their high cytotoxicity, alpha particles should be preferred to beta particles and X-rays to overcome radiation resistance. However, clinical studies showed that TAT might be efficient also in quite large tumors, and biological effects have been observed also away from irradiated cells. These distant effects are called bystander effects when occurring at short distance (<1 mm), and systemic effects when occurring at much longer distance. Systemic effects implicate the immune system. These findings showed that cells can die without receiving any radiation dose, and that a more complex and integrated view of radiobiology is required. This includes the notion that the direct, bystander and systemic responses cannot be dissociated because DNA damage is intimately linked to bystander effects and immune response. Here, we provide a brief overview of the paradigms that need to be revisited.
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Affiliation(s)
- Jean-Pierre Pouget
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Julie Constanzo
- Institut de Recherche en Cancérologie de Montpellier (IRCM), Inserm U1194, Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France
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Checker R, Patwardhan RS, Jayakumar S, Maurya DK, Bandekar M, Sharma D, Sandur SK. Chemical and biological basis for development of novel radioprotective drugs for cancer therapy. Free Radic Res 2021; 55:595-625. [PMID: 34181503 DOI: 10.1080/10715762.2021.1876854] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ionizing radiation (IR) causes chemical changes in biological systems through direct interaction with the macromolecules or by causing radiolysis of water. This property of IR is harnessed in the clinic for radiotherapy in almost 50% of cancers patients. Despite the advent of stereotactic radiotherapy instruments and other advancements in shielding techniques, the inadvertent deposition of radiation dose in the surrounding normal tissue can cause late effects of radiation injury in normal tissues. Radioprotectors, which are chemical or biological agents, can reduce or mitigate these toxic side-effects of radiotherapy in cancer patients and also during radiation accidents. The desired characteristics of an ideal radioprotector include low chemical toxicity, high risk to benefit ratio and specific protection of normal cells against the harmful effects of radiation without compromising the cytotoxic effects of IR on cancer cells. Since reactive oxygen species (ROS) are the major contributors of IR mediated toxicity, plethora of studies have highlighted the potential role of antioxidants to protect against IR induced damage. However, owing to the lack of any clinically approved radioprotector against whole body radiation, researchers have shifted the focus toward finding alternate targets that could be exploited for the development of novel agents. The present review provides a comprehensive insight in to the different strategies, encompassing prime molecular targets, which have been employed to develop radiation protectors/countermeasures. It is anticipated that understanding such factors will lead to the development of novel strategies for increasing the outcome of radiotherapy by minimizing normal tissue toxicity.
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Affiliation(s)
- Rahul Checker
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Raghavendra S Patwardhan
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Sundarraj Jayakumar
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
| | - Dharmendra Kumar Maurya
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Mayuri Bandekar
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India
| | - Deepak Sharma
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
| | - Santosh K Sandur
- Radiation Biology & Health Sciences Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, India.,Homi Bhabha National Institute, Anushaktinagar, Mumbai, India
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38
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Zhou Y, Gorfe AA, Hancock JF. RAS Nanoclusters Selectively Sort Distinct Lipid Headgroups and Acyl Chains. Front Mol Biosci 2021; 8:686338. [PMID: 34222339 PMCID: PMC8245699 DOI: 10.3389/fmolb.2021.686338] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022] Open
Abstract
RAS proteins are lipid-anchored small GTPases that switch between the GTP-bound active and GDP-bound inactive states. RAS isoforms, including HRAS, NRAS and splice variants KRAS4A and KRAS4B, are some of the most frequently mutated proteins in cancer. In particular, constitutively active mutants of KRAS comprise ∼80% of all RAS oncogenic mutations and are found in 98% of pancreatic, 45% of colorectal and 31% of lung tumors. Plasma membrane (PM) is the primary location of RAS signaling in biology and pathology. Thus, a better understanding of how RAS proteins localize to and distribute on the PM is critical to better comprehend RAS biology and to develop new strategies to treat RAS pathology. In this review, we discuss recent findings on how RAS proteins sort lipids as they undergo macromolecular assembly on the PM. We also discuss how RAS/lipid nanoclusters serve as signaling platforms for the efficient recruitment of effectors and signal transduction, and how perturbing the PM biophysical properties affect the spatial distribution of RAS isoforms and their functions.
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Affiliation(s)
- Yong Zhou
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, United States
| | - Alemayehu A. Gorfe
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, United States
| | - John F. Hancock
- Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, TX, United States
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39
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Quinville BM, Deschenes NM, Ryckman AE, Walia JS. A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis. Int J Mol Sci 2021; 22:ijms22115793. [PMID: 34071409 PMCID: PMC8198874 DOI: 10.3390/ijms22115793] [Citation(s) in RCA: 143] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/23/2021] [Accepted: 05/24/2021] [Indexed: 12/16/2022] Open
Abstract
Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer’s and Parkinson’s disease, and lysosomal storage disorders.
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40
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Poczobutt JM, Mikosz AM, Poirier C, Beatman EL, Serban KA, Gally F, Cao D, McCubbrey AL, Cornell CF, Schweitzer KS, Berdyshev EV, Bronova IA, Paris F, Petrache I. Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency. Am J Respir Cell Mol Biol 2021; 64:629-640. [PMID: 33662226 PMCID: PMC8086042 DOI: 10.1165/rcmb.2020-0229oc] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 02/12/2021] [Indexed: 11/24/2022] Open
Abstract
Deficiency of ASM (acid sphingomyelinase) causes the lysosomal storage Niemann-Pick disease (NPD). Patients with NPD type B may develop progressive interstitial lung disease with frequent respiratory infections. Although several investigations using the ASM-deficient (ASMKO) mouse NPD model revealed inflammation and foamy macrophages, there is little insight into the pathogenesis of NPD-associated lung disease. Using ASMKO mice, we report that ASM deficiency is associated with a complex inflammatory phenotype characterized by marked accumulation of monocyte-derived CD11b+ macrophages and expansion of airspace/alveolar CD11c+ CD11b- macrophages, both with increased size, granularity, and foaminess. Both the alternative and classical pathways were activated, with decreased in situ phagocytosis of opsonized (Fc-coated) targets, preserved clearance of apoptotic cells (efferocytosis), secretion of Th2 cytokines, increased CD11c+/CD11b+ cells, and more than a twofold increase in lung and plasma proinflammatory cytokines. Macrophages, neutrophils, eosinophils, and noninflammatory lung cells of ASMKO lungs also exhibited marked accumulation of chitinase-like protein Ym1/2, which formed large eosinophilic polygonal Charcot-Leyden-like crystals. In addition to providing insight into novel features of lung inflammation that may be associated with NPD, our report provides a novel connection between ASM and the development of crystal-associated lung inflammation with alterations in macrophage biology.
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MESH Headings
- Animals
- CD11 Antigens/genetics
- CD11 Antigens/immunology
- CD11b Antigen/genetics
- CD11b Antigen/immunology
- Cell Size
- Chitinases/genetics
- Chitinases/immunology
- Disease Models, Animal
- Eosinophils/immunology
- Eosinophils/pathology
- Female
- Gene Expression
- Glycoproteins/genetics
- Glycoproteins/immunology
- Humans
- Lectins/genetics
- Lectins/immunology
- Lung/immunology
- Lung/pathology
- Lysophospholipase/genetics
- Lysophospholipase/immunology
- Macrophages/immunology
- Macrophages/pathology
- Macrophages, Alveolar/immunology
- Macrophages, Alveolar/pathology
- Male
- Mice
- Mice, Knockout
- Neutrophils/immunology
- Neutrophils/pathology
- Niemann-Pick Disease, Type A/enzymology
- Niemann-Pick Disease, Type A/genetics
- Niemann-Pick Disease, Type A/immunology
- Niemann-Pick Disease, Type A/pathology
- Niemann-Pick Disease, Type B/enzymology
- Niemann-Pick Disease, Type B/genetics
- Niemann-Pick Disease, Type B/immunology
- Niemann-Pick Disease, Type B/pathology
- Phagocytosis
- Pneumonia/enzymology
- Pneumonia/genetics
- Pneumonia/immunology
- Pneumonia/pathology
- Sphingomyelin Phosphodiesterase/deficiency
- Sphingomyelin Phosphodiesterase/genetics
- Sphingomyelin Phosphodiesterase/immunology
- Th1-Th2 Balance/genetics
- beta-N-Acetylhexosaminidases/genetics
- beta-N-Acetylhexosaminidases/immunology
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Affiliation(s)
| | | | | | | | - Karina A. Serban
- National Jewish Health, Denver, Colorado
- University of Colorado, Denver, Colorado
| | - Fabienne Gally
- National Jewish Health, Denver, Colorado
- University of Colorado, Denver, Colorado
| | | | | | | | - Kelly S. Schweitzer
- National Jewish Health, Denver, Colorado
- University of Colorado, Denver, Colorado
| | | | | | - François Paris
- Institut de Cancérologie de l’Ouest, Saint-Herblain, France; and
- Le Regional Center for Research in Cancerology and Immunology Nantes/Angers, Université de Nantes, Nantes, France
| | - Irina Petrache
- National Jewish Health, Denver, Colorado
- Indiana University, Indianapolis, Indiana
- University of Colorado, Denver, Colorado
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41
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Acid-Sphingomyelinase Triggered Fluorescently Labeled Sphingomyelin Containing Liposomes in Tumor Diagnosis after Radiation-Induced Stress. Int J Mol Sci 2021; 22:ijms22083864. [PMID: 33917976 PMCID: PMC8068344 DOI: 10.3390/ijms22083864] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 11/21/2022] Open
Abstract
In liposomal delivery, a big question is how to release the loaded material into the correct place. Here, we will test the targeting and release abilities of our sphingomyelin-consisting liposome. A change in release parameters can be observed when sphingomyelin-containing liposome is treated with sphingomyelinase enzyme. Sphingomyelinase is known to be endogenously released from the different cells in stress situations. We assume the effective enzyme treatment will weaken the liposome making it also leakier. To test the release abilities of the SM-liposome, we developed several fluorescence-based experiments. In in vitro studies, we used molecular quenching to study the sphingomyelinase enzyme-based release from the liposomes. We could show that the enzyme treatment releases loaded fluorescent markers from sphingomyelin-containing liposomes. Moreover, the release correlated with used enzymatic activities. We studied whether the stress-related enzyme expression is increased if the cells are treated with radiation as a stress inducer. It appeared that the radiation caused increased enzymatic activity. We studied our liposomes’ biodistribution in the animal tumor model when the tumor was under radiation stress. Increased targeting of the fluorescent marker loaded to our liposomes could be found on the site of cancer. The liposomal targeting in vivo could be improved by radiation. Based on our studies, we propose sphingomyelin-containing liposomes can be used as a controlled release system sensitive to cell stress.
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42
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Kim JL, Mestre B, Shin SH, Futerman AH. Ceramide synthases: Reflections on the impact of Dr. Lina M. Obeid. Cell Signal 2021; 82:109958. [PMID: 33607256 DOI: 10.1016/j.cellsig.2021.109958] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 02/12/2021] [Accepted: 02/12/2021] [Indexed: 12/16/2022]
Abstract
Sphingolipids are a family of lipids that are critical to cell function and survival. Much of the recent work done on sphingolipids has been performed by a closely-knit family of sphingolipid researchers, which including our colleague, Dr. Lina Obeid, who recently passed away. We now briefly review where the sphingolipid field stands today, focusing in particular on areas of sphingolipid research to which Dr. Obeid made valued contributions. These include the 'many-worlds' view of ceramides and the role of a key enzyme in the sphingolipid biosynthetic pathway, namely the ceramide synthases (CerS). The CerS contain a number of functional domains and also interact with a number of other proteins in lipid metabolic pathways, fulfilling Dr. Obeid's prophecy that ceramides, and the enzymes that generate ceramides, form the critical hub of the sphingolipid metabolic pathway.
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Affiliation(s)
- Jiyoon L Kim
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Beatriz Mestre
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Sun-Hye Shin
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel
| | - Anthony H Futerman
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
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43
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Simon MV, Basu SK, Qaladize B, Grambergs R, Rotstein NP, Mandal N. Sphingolipids as critical players in retinal physiology and pathology. J Lipid Res 2021; 62:100037. [PMID: 32948663 PMCID: PMC7933806 DOI: 10.1194/jlr.tr120000972] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [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: 09/04/2020] [Indexed: 12/24/2022] Open
Abstract
Sphingolipids have emerged as bioactive lipids involved in the regulation of many physiological and pathological processes. In the retina, they have been established to participate in numerous processes, such as neuronal survival and death, proliferation and migration of neuronal and vascular cells, inflammation, and neovascularization. Dysregulation of sphingolipids is therefore crucial in the onset and progression of retinal diseases. This review examines the involvement of sphingolipids in retinal physiology and diseases. Ceramide (Cer) has emerged as a common mediator of inflammation and death of neuronal and retinal pigment epithelium cells in animal models of retinopathies such as glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa. Sphingosine-1-phosphate (S1P) has opposite roles, preventing photoreceptor and ganglion cell degeneration but also promoting inflammation, fibrosis, and neovascularization in AMD, glaucoma, and pro-fibrotic disorders. Alterations in Cer, S1P, and ceramide 1-phosphate may also contribute to uveitis. Notably, use of inhibitors that either prevent Cer increase or modulate S1P signaling, such as Myriocin, desipramine, and Fingolimod (FTY720), preserves neuronal viability and retinal function. These findings underscore the relevance of alterations in the sphingolipid metabolic network in the etiology of multiple retinopathies and highlight the potential of modulating their metabolism for the design of novel therapeutic approaches.
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Affiliation(s)
- M Victoria Simon
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Departamento De Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS), Argentine National Research Council (CONICET), Bahía Blanca, Argentina
| | - Sandip K Basu
- Departments of Ophthalmology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Bano Qaladize
- Departments of Ophthalmology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Richard Grambergs
- Departments of Ophthalmology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Nora P Rotstein
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Departamento De Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS), Argentine National Research Council (CONICET), Bahía Blanca, Argentina.
| | - Nawajes Mandal
- Departments of Ophthalmology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
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Thayyullathil F, Cheratta AR, Alakkal A, Subburayan K, Pallichankandy S, Hannun YA, Galadari S. Acid sphingomyelinase-dependent autophagic degradation of GPX4 is critical for the execution of ferroptosis. Cell Death Dis 2021; 12:26. [PMID: 33414455 PMCID: PMC7791123 DOI: 10.1038/s41419-020-03297-w] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 01/29/2023]
Abstract
Ferroptosis is a type of regulated cell death characterized by ROS accumulation and devastating lipid peroxidation (LPO). The role of acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, in the induction of apoptosis has been studied; however, to date its role in ferroptosis is unclear. In this study, we report that ASM plays a hitherto unanticipated role in promoting ferroptosis. Mechanistically, Erastin (Era) treatment results in the activation of ASM and generation of ceramide, which are required for the Era-induced reactive oxygen species (ROS) generation and LPO. Inhibition of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) or removal of intracellular ROS, significantly reduced Era-induced ASM activation, suggesting that NADPH oxidase-derived ROS regulated ASM-initiated redox signaling in a positive feedback manner. Moreover, ASM-mediated activation of autophagy plays a critical role in ferroptosis inducers (FINs)-induced glutathione peroxidase 4 (GPX4) degradation and ferroptosis activation. Genetic or pharmacological inhibition of ASM diminishes Era-induced features of autophagy, GPX4 degradation, LPO, and subsequent ferroptosis. Importantly, genetic activation of ASM increases ferroptosis in cancer cells induced by various FINs. Collectively, these findings reveal that ASM plays a novel role in ferroptosis that could be exploited to improve pathological conditions that link to ferroptosis.
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Affiliation(s)
- Faisal Thayyullathil
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P. O. Box. 129188, Abu Dhabi, UAE
| | - Anees Rahman Cheratta
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P. O. Box. 129188, Abu Dhabi, UAE
| | - Ameer Alakkal
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P. O. Box. 129188, Abu Dhabi, UAE
| | - Karthikeyan Subburayan
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P. O. Box. 129188, Abu Dhabi, UAE
| | - Siraj Pallichankandy
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P. O. Box. 129188, Abu Dhabi, UAE
| | - Yusuf A Hannun
- Departments of Medicine and Biochemistry, Stony Brook University, Stony Brook, New York, 11794, USA
| | - Sehamuddin Galadari
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P. O. Box. 129188, Abu Dhabi, UAE.
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Peñate Medina T, Gerle M, Humbert J, Chu H, Köpnick AL, Barkmann R, Garamus VM, Sanz B, Purcz N, Will O, Appold L, Damm T, Suojanen J, Arnold P, Lucius R, Willumeit-Römer R, Açil Y, Wiltfang J, Goya GF, Glüer CC, Peñate Medina O. Lipid-Iron Nanoparticle with a Cell Stress Release Mechanism Combined with a Local Alternating Magnetic Field Enables Site-Activated Drug Release. Cancers (Basel) 2020; 12:cancers12123767. [PMID: 33327621 PMCID: PMC7765112 DOI: 10.3390/cancers12123767] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/02/2020] [Accepted: 12/02/2020] [Indexed: 11/16/2022] Open
Abstract
Most available cancer chemotherapies are based on systemically administered small organic molecules, and only a tiny fraction of the drug reaches the disease site. The approach causes significant side effects and limits the outcome of the therapy. Targeted drug delivery provides an alternative to improve the situation. However, due to the poor release characteristics of the delivery systems, limitations remain. This report presents a new approach to address the challenges using two fundamentally different mechanisms to trigger the release from the liposomal carrier. We use an endogenous disease marker, an enzyme, combined with an externally applied magnetic field, to open the delivery system at the correct time only in the disease site. This site-activated release system is a novel two-switch nanomachine that can be regulated by a cell stress-induced enzyme at the cellular level and be remotely controlled using an applied magnetic field. We tested the concept using sphingomyelin-containing liposomes encapsulated with indocyanine green, fluorescent marker, or the anticancer drug cisplatin. We engineered the liposomes by adding paramagnetic beads to act as a receiver of outside magnetic energy. The developed multifunctional liposomes were characterized in vitro in leakage studies and cell internalization studies. The release system was further studied in vivo in imaging and therapy trials using a squamous cell carcinoma tumor in the mouse as a disease model. In vitro studies showed an increased release of loaded material when stress-related enzyme and magnetic field was applied to the carrier liposomes. The theranostic liposomes were found in tumors, and the improved therapeutic effect was shown in the survival studies.
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Affiliation(s)
- Tuula Peñate Medina
- Section Biomedical Imaging, Department of Radiology and Neuroradiology Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (T.P.M.); (J.H.); (A.-L.K.); (R.B.); (O.W.); (T.D.); (C.C.G.)
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, 24105 Kiel, Germany;
| | - Mirko Gerle
- Klinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (M.G.); (H.C.); (N.P.); (Y.A.); (J.W.)
| | - Jana Humbert
- Section Biomedical Imaging, Department of Radiology and Neuroradiology Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (T.P.M.); (J.H.); (A.-L.K.); (R.B.); (O.W.); (T.D.); (C.C.G.)
| | - Hanwen Chu
- Klinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (M.G.); (H.C.); (N.P.); (Y.A.); (J.W.)
- Department of Oral and Maxillofacial Surgery, Second Affiliated Hospital, Zhejiang University, Hangzhou 310058, China
| | - Anna-Lena Köpnick
- Section Biomedical Imaging, Department of Radiology and Neuroradiology Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (T.P.M.); (J.H.); (A.-L.K.); (R.B.); (O.W.); (T.D.); (C.C.G.)
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, 24105 Kiel, Germany;
| | - Reinhard Barkmann
- Section Biomedical Imaging, Department of Radiology and Neuroradiology Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (T.P.M.); (J.H.); (A.-L.K.); (R.B.); (O.W.); (T.D.); (C.C.G.)
| | - Vasil M. Garamus
- Helmholtz-Zentrum Geesthacht, Zentrum für Material- und Küstenforschung GmbH, Max Planck Straße 1, 21502 Geesthacht, Germany; (V.M.G.); (R.W.-R.)
| | - Beatriz Sanz
- Institute of Nanoscience of Aragon (INA) and Condensed Matter Physics Dept., University of Zaragoza, C.P. 50.018 Zaragoza, Spain; (B.S.); (G.F.G.)
| | - Nicolai Purcz
- Klinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (M.G.); (H.C.); (N.P.); (Y.A.); (J.W.)
| | - Olga Will
- Section Biomedical Imaging, Department of Radiology and Neuroradiology Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (T.P.M.); (J.H.); (A.-L.K.); (R.B.); (O.W.); (T.D.); (C.C.G.)
| | - Lia Appold
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, 24105 Kiel, Germany;
| | - Timo Damm
- Section Biomedical Imaging, Department of Radiology and Neuroradiology Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (T.P.M.); (J.H.); (A.-L.K.); (R.B.); (O.W.); (T.D.); (C.C.G.)
| | - Juho Suojanen
- Cleft Palate and Craniofacial Center, Department of Plastic Surgery, Helsinki University Hospital, 00029 HUS Helsinki, Finland;
- Päijät-Häme Joint Authority for Health and Wellbeing, Department of Oral and Maxillo-Facial Surgery, 15850 Lahti, Finland
| | - Philipp Arnold
- Anatomical Institute, Christian-Albrechts-University Kiel, 24105 Kiel, Germany or (P.A.); (R.L.)
| | - Ralph Lucius
- Anatomical Institute, Christian-Albrechts-University Kiel, 24105 Kiel, Germany or (P.A.); (R.L.)
| | - Regina Willumeit-Römer
- Helmholtz-Zentrum Geesthacht, Zentrum für Material- und Küstenforschung GmbH, Max Planck Straße 1, 21502 Geesthacht, Germany; (V.M.G.); (R.W.-R.)
| | - Yahya Açil
- Klinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (M.G.); (H.C.); (N.P.); (Y.A.); (J.W.)
| | - Joerg Wiltfang
- Klinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (M.G.); (H.C.); (N.P.); (Y.A.); (J.W.)
| | - Gerardo F. Goya
- Institute of Nanoscience of Aragon (INA) and Condensed Matter Physics Dept., University of Zaragoza, C.P. 50.018 Zaragoza, Spain; (B.S.); (G.F.G.)
| | - Claus C. Glüer
- Section Biomedical Imaging, Department of Radiology and Neuroradiology Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (T.P.M.); (J.H.); (A.-L.K.); (R.B.); (O.W.); (T.D.); (C.C.G.)
| | - Oula Peñate Medina
- Section Biomedical Imaging, Department of Radiology and Neuroradiology Universitätsklinikum Schleswig-Holstein Campus Kiel, Christian Albrechts Universität zu Kiel, 24105 Kiel, Germany; (T.P.M.); (J.H.); (A.-L.K.); (R.B.); (O.W.); (T.D.); (C.C.G.)
- Institute for Experimental Cancer Research, Christian-Albrechts-University Kiel, 24105 Kiel, Germany;
- Correspondence: ; Tel.: +491605559588
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Lee SC, Lin KH, Balogh A, Norman DD, Bavaria M, Kuo B, Yue J, Balázs L, Benyó Z, Tigyi G. Dysregulation of lysophospholipid signaling by p53 in malignant cells and the tumor microenvironment. Cell Signal 2020; 78:109850. [PMID: 33253914 DOI: 10.1016/j.cellsig.2020.109850] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/20/2020] [Accepted: 11/22/2020] [Indexed: 12/22/2022]
Abstract
The TP53 gene has been widely studied for its roles in cell cycle control, maintaining genome stability, activating repair mechanisms upon DNA damage, and initiating apoptosis should repair mechanisms fail. Thus, it is not surprising that mutations of p53 are the most common genetic alterations found in human cancer. Emerging evidence indicates that dysregulation of lipid metabolism by p53 can have a profound impact not only on cancer cells but also cells of the tumor microenvironment (TME). In particular, intermediates of the sphingolipid and lysophospholipid pathways regulate many cellular responses common to p53 such as cell survival, migration, DNA damage repair and apoptosis. The majority of these cellular events become dysregulated in cancer as well as cell senescence. In this review, we will provide an account on the seminal contributions of Prof. Lina Obeid, who deciphered the crosstalk between p53 and the sphingolipid pathway particularly in modulating DNA damage repair and apoptosis in non-transformed as well as transformed cells. We will also provide insights on the integrative role of p53 with the lysophosphatidic acid (LPA) signaling pathway in cancer progression and TME regulation.
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Affiliation(s)
- Sue Chin Lee
- Department of Physiology, University of Tennessee Health Science Center Memphis, Van Vleet Cancer Research Building, 3 N. Dunlap Street, Memphis, TN 38163, USA
| | - Kuan-Hung Lin
- Department of Physiology, University of Tennessee Health Science Center Memphis, Van Vleet Cancer Research Building, 3 N. Dunlap Street, Memphis, TN 38163, USA
| | - Andrea Balogh
- Department of Physiology, University of Tennessee Health Science Center Memphis, Van Vleet Cancer Research Building, 3 N. Dunlap Street, Memphis, TN 38163, USA; Institute of Translational Medicine, Semmelweis University, POB 2, H-1428 Budapest, Hungary
| | - Derek D Norman
- Department of Physiology, University of Tennessee Health Science Center Memphis, Van Vleet Cancer Research Building, 3 N. Dunlap Street, Memphis, TN 38163, USA
| | - Mitul Bavaria
- Department of Physiology, University of Tennessee Health Science Center Memphis, Van Vleet Cancer Research Building, 3 N. Dunlap Street, Memphis, TN 38163, USA
| | - Bryan Kuo
- Department of Physiology, University of Tennessee Health Science Center Memphis, Van Vleet Cancer Research Building, 3 N. Dunlap Street, Memphis, TN 38163, USA
| | - Junming Yue
- Department of Pathology, University of Tennessee Health Science Center Memphis, USA
| | - Louisa Balázs
- Department of Pathology, University of Tennessee Health Science Center Memphis, USA
| | - Zoltán Benyó
- Institute of Translational Medicine, Semmelweis University, POB 2, H-1428 Budapest, Hungary
| | - Gábor Tigyi
- Department of Physiology, University of Tennessee Health Science Center Memphis, Van Vleet Cancer Research Building, 3 N. Dunlap Street, Memphis, TN 38163, USA; Institute of Translational Medicine, Semmelweis University, POB 2, H-1428 Budapest, Hungary.
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Hagemann N, Mohamud Yusuf A, Martiny C, Zhang X, Kleinschnitz C, Gunzer M, Kolesnick R, Gulbins E, Hermann DM. Homozygous Smpd1 deficiency aggravates brain ischemia/ reperfusion injury by mechanisms involving polymorphonuclear neutrophils, whereas heterozygous Smpd1 deficiency protects against mild focal cerebral ischemia. Basic Res Cardiol 2020; 115:64. [PMID: 33057972 PMCID: PMC7560939 DOI: 10.1007/s00395-020-00823-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/15/2020] [Indexed: 12/29/2022]
Abstract
By cleaving sphingomyelin into ceramide, which is an essential component of plasma membrane microdomains, acid sphingomyelinase (Asm) pivotally controls cell signaling. To define how the activation of the Asm/ceramide pathway, which occurs within seconds to minutes upon stress stimuli, influences brain ischemia/reperfusion (I/R) injury, we exposed male and female wildtype mice carrying both alleles of Asm's gene sphingomyelinase phosphodiesterase-1 (Smpd1+/+), heterozygously Asm-deficient mice (Smpd1+/-) and homozygously Asm-deficient mice (Smpd1-/-) of different age (8, 12 or 16 weeks) to 30, 60 or 90 min intraluminal middle cerebral artery occlusion (MCAO). For studying the contribution of brain-invading polymorphonuclear neutrophils (PMN) to I/R injury, PMNs were depleted by delivery of a PMN-specific Ly6G antibody. In male and female mice exposed to 30 min, but not 60 or 90 min MCAO, homozygous Smpd1-/- consistently increased I/R injury, blood-brain barrier permeability and brain leukocyte and PMN infiltration, whereas heterozygous Smpd1+/- reduced I/R injury. Increased abundance of the intercellular leukocyte adhesion molecule ICAM-1 was noted on cerebral microvessels of Smpd1-/- mice. PMN depletion by anti-Ly6G delivery prevented the exacerbation of I/R injury in Smpd1-/- compared with wildtype mice and reduced brain leukocyte infiltrates. Our results show that Asm tempers leukocyte entry into the reperfused ischemic brain, thereby attenuating I/R injury.
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Affiliation(s)
- Nina Hagemann
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Ayan Mohamud Yusuf
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Carlotta Martiny
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Xiaoni Zhang
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Christoph Kleinschnitz
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Matthias Gunzer
- Institute of Experimental Immunology and Imaging, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | | | - Erich Gulbins
- Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany
| | - Dirk M Hermann
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, 45147, Essen, Germany.
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Szlasa W, Zendran I, Zalesińska A, Tarek M, Kulbacka J. Lipid composition of the cancer cell membrane. J Bioenerg Biomembr 2020; 52:321-342. [PMID: 32715369 PMCID: PMC7520422 DOI: 10.1007/s10863-020-09846-4] [Citation(s) in RCA: 222] [Impact Index Per Article: 44.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 07/10/2020] [Indexed: 12/12/2022]
Abstract
Cancer cell possesses numerous adaptations to resist the immune system response and chemotherapy. One of the most significant properties of the neoplastic cells is the altered lipid metabolism, and consequently, the abnormal cell membrane composition. Like in the case of phosphatidylcholine, these changes result in the modulation of certain enzymes and accumulation of energetic material, which could be used for a higher proliferation rate. The changes are so prominent, that some lipids, such as phosphatidylserines, could even be considered as the cancer biomarkers. Additionally, some changes of biophysical properties of cell membranes lead to the higher resistance to chemotherapy, and finally to the disturbances in signalling pathways. Namely, the increased levels of certain lipids, like for instance phosphatidylserine, lead to the attenuation of the immune system response. Also, changes in lipid saturation prevent the cells from demanding conditions of the microenvironment. Particularly interesting is the significance of cell membrane cholesterol content in the modulation of metastasis. This review paper discusses the roles of each lipid type in cancer physiology. The review combined theoretical data with clinical studies to show novel therapeutic options concerning the modulation of cell membranes in oncology.
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Affiliation(s)
- Wojciech Szlasa
- Faculty of Medicine, Wroclaw Medical University, Wrocław, Poland
| | - Iga Zendran
- Faculty of Medicine, Wroclaw Medical University, Wrocław, Poland
| | | | - Mounir Tarek
- Université de Lorraine, CNRS, LPCT, F-54000, Nancy, France
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wrocław, Poland.
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Saito EY, Saito K, Hishiki T, Takenouchi A, Saito T, Sato Y, Terui K, Matsunaga T, Shirasawa H, Yoshida H. Sindbis viral structural protein cytotoxicity on human neuroblastoma cells. Pediatr Surg Int 2020; 36:1173-1180. [PMID: 32696122 PMCID: PMC7474708 DOI: 10.1007/s00383-020-04719-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/14/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE Oncolytic viral therapy for neuroblastoma (NB) cells with Sindbis virus (SINV) is a promising strategy for treating high-risk NB. Here, we evaluated the possibility of using SINV structural proteins as therapeutic agents for NB since UV-inactivated SINV could induce cytopathogenic effects. METHODS The cytotoxicity of UV-inactivated SINV toward human NB cell lines NB69, NGP, GOTO, NLF, SK-N-SH, SH-SY5Y, CHP134, NB-1, IMR32, and RT-BM-1 were analyzed. Apoptosis was confirmed by TUNEL assays. To determine the components of SINV responsible for the cytotoxicity of UV-inactivated SINV, expression vectors encoding the structural proteins, namely capsid, E2, and E1, were transfected in NB cells. Cytotoxicity was evaluated by MTT assays. RESULTS UV-inactivated SINV elicited more significant cytotoxicity in NB69, NGP, and RT-BM-1 than in normal human fibroblasts. Results of the transfection experiments showed that all NB cell lines susceptible to UV-inactivated SINV were highly susceptible to the E1 protein, whereas fibroblasts transfected with vectors harboring capsid, E1, or E2 were not. CONCLUSIONS We demonstrated that the cytotoxicity of the UV-inactivated SINV is due to apoptosis induced by the E1 structural protein of SINV, which can be used selectively as a therapeutic agent for NB.
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Affiliation(s)
- Eriko Y. Saito
- grid.136304.30000 0004 0370 1101Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
| | - Kengo Saito
- grid.136304.30000 0004 0370 1101Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
| | - Tomoro Hishiki
- grid.136304.30000 0004 0370 1101Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
| | - Ayako Takenouchi
- grid.136304.30000 0004 0370 1101Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
| | - Takeshi Saito
- grid.136304.30000 0004 0370 1101Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
| | - Yoshiharu Sato
- grid.136304.30000 0004 0370 1101Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
| | - Keita Terui
- grid.136304.30000 0004 0370 1101Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
| | - Tadashi Matsunaga
- grid.136304.30000 0004 0370 1101Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
| | - Hiroshi Shirasawa
- grid.136304.30000 0004 0370 1101Molecular Virology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
| | - Hideo Yoshida
- grid.136304.30000 0004 0370 1101Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670 Japan
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50
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Hawkins CC, Ali T, Ramanadham S, Hjelmeland AB. Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate. Biomolecules 2020; 10:E1357. [PMID: 32977496 PMCID: PMC7598277 DOI: 10.3390/biom10101357] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/18/2020] [Accepted: 09/20/2020] [Indexed: 01/05/2023] Open
Abstract
Glioblastoma (GBM) is a primary malignant brain tumor with a dismal prognosis, partially due to our inability to completely remove and kill all GBM cells. Rapid tumor recurrence contributes to a median survival of only 15 months with the current standard of care which includes maximal surgical resection, radiation, and temozolomide (TMZ), a blood-brain barrier (BBB) penetrant chemotherapy. Radiation and TMZ cause sphingomyelinases (SMase) to hydrolyze sphingomyelins to generate ceramides, which induce apoptosis. However, cells can evade apoptosis by converting ceramides to sphingosine-1-phosphate (S1P). S1P has been implicated in a wide range of cancers including GBM. Upregulation of S1P has been linked to the proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. To mediate their biological effects, SMases and S1P modulate signaling via phospholipase C (PLC) and phospholipase D (PLD). In addition, both SMase and S1P may alter the integrity of the BBB leading to infiltration of tumor-promoting immune populations. SMase activity has been associated with tumor evasion of the immune system, while S1P creates a gradient for trafficking of innate and adaptive immune cells. This review will explore the role of sphingolipid metabolism and pharmacological interventions in GBM and metastatic brain tumors with a focus on SMase and S1P.
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Affiliation(s)
- Cyntanna C. Hawkins
- Department of Cell, Developmental, and Integrative Biology, University of Birmingham at Alabama, Birmingham, AL 35233, USA; (C.C.H.); (S.R.)
| | - Tomader Ali
- Research Department, Imperial College London Diabetes Centre, Abu Dhabi P.O. Box 48338, UAE;
| | - Sasanka Ramanadham
- Department of Cell, Developmental, and Integrative Biology, University of Birmingham at Alabama, Birmingham, AL 35233, USA; (C.C.H.); (S.R.)
- Comprehensive Diabetes Center, University of Birmingham at Alabama, Birmingham, AL 35294, USA
| | - Anita B. Hjelmeland
- Department of Cell, Developmental, and Integrative Biology, University of Birmingham at Alabama, Birmingham, AL 35233, USA; (C.C.H.); (S.R.)
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