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Hu T, Han F, An Z. Comprehensive profiling of serum glycosphingolipids to discover the diagnostic biomarkers of lung cancer and uncover the variation of glycosphingolipid networks in different lung cancer subtypes. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2024; 16:7873-7887. [PMID: 39479885 DOI: 10.1039/d4ay01685h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Glycosphingolipids are glycolipid complexes formed by an oligosaccharide chain covalently linked to a ceramide backbone and play important roles in the occurrence and metastasis of lung cancer. In this study, an UHPLC-HRMS method was developed for the comprehensive profiling of glycosphingolipids, with an in-house library constructed for data interpretation. Serum glycosphingolipids were profiled in 31 healthy controls (HCs) and 92 lung cancer patients with different pathologic subtypes. Over 1700 glycosphingolipids were detected in human serum based on the novel method. A total of 567 differential glycosphingolipids (adjusted P < 0.05, and fold change > 2) were found between lung cancer patients and HCs. Glycosphingolipids can be used as potential biomarkers for lung cancer diagnosis, with sensitivity much higher than that of traditional serum tumor markers. The levels of most glycosphingolipids in squamous cell carcinoma (Squa) were significantly lower than those in small cell lung cancer (SCLC) and adenocarcinoma (Aden). The highest Cer1P abundance in SCLC patients among the three different subtypes of lung cancer was thought to be related to the high malignancy and metastasis of SCLC. An artificial neural network (ANN) model was constructed for the discrimination of the three different subtypes of lung cancer, with accuracy higher than 93%. Beyond providing biomarkers and statistical models for the diagnosis of lung cancer and discrimination of lung cancer subtypes, this study uncovered the variation of glycosphingolipid networks in different subtypes of lung cancer and thereby provided a novel insight to study the pathogenesis of lung cancer and explore therapeutic targets.
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Affiliation(s)
- Ting Hu
- Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti South Road, Chaoyang District, Beijing 100020, PR China.
| | - Feifei Han
- Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti South Road, Chaoyang District, Beijing 100020, PR China.
| | - Zhuoling An
- Beijing Chao-Yang Hospital, Capital Medical University, No. 8 Gongti South Road, Chaoyang District, Beijing 100020, PR China.
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Guo Y, Xue L, Tang W, Xiong J, Chen D, Dai Y, Wu C, Wei S, Dai J, Wu M, Wang S. Ovarian microenvironment: challenges and opportunities in protecting against chemotherapy-associated ovarian damage. Hum Reprod Update 2024; 30:614-647. [PMID: 38942605 PMCID: PMC11369228 DOI: 10.1093/humupd/dmae020] [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: 10/30/2023] [Revised: 04/27/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Chemotherapy-associated ovarian damage (CAOD) is one of the most feared short- and long-term side effects of anticancer treatment in premenopausal women. Accumulating detailed data show that different chemotherapy regimens can lead to disturbance of ovarian hormone levels, reduced or lost fertility, and an increased risk of early menopause. Previous studies have often focused on the direct effects of chemotherapeutic drugs on ovarian follicles, such as direct DNA damage-mediated apoptotic death and primordial follicle burnout. Emerging evidence has revealed an imbalance in the ovarian microenvironment during chemotherapy. The ovarian microenvironment provides nutritional support and transportation of signals that stimulate the growth and development of follicles, ovulation, and corpus luteum formation. The close interaction between the ovarian microenvironment and follicles can determine ovarian function. Therefore, designing novel and precise strategies to manipulate the ovarian microenvironment may be a new strategy to protect ovarian function during chemotherapy. OBJECTIVE AND RATIONALE This review details the changes that occur in the ovarian microenvironment during chemotherapy and emphasizes the importance of developing new therapeutics that protect ovarian function by targeting the ovarian microenvironment during chemotherapy. SEARCH METHODS A comprehensive review of the literature was performed by searching PubMed up to April 2024. Search terms included 'ovarian microenvironment' (ovarian extracellular matrix, ovarian stromal cells, ovarian interstitial, ovarian blood vessels, ovarian lymphatic vessels, ovarian macrophages, ovarian lymphocytes, ovarian immune cytokines, ovarian oxidative stress, ovarian reactive oxygen species, ovarian senescence cells, ovarian senescence-associated secretory phenotypes, ovarian oogonial stem cells, ovarian stem cells), terms related to ovarian function (reproductive health, fertility, infertility, fecundity, ovarian reserve, ovarian function, menopause, decreased ovarian reserve, premature ovarian insufficiency/failure), and terms related to chemotherapy (cyclophosphamide, lfosfamide, chlormethine, chlorambucil, busulfan, melphalan, procarbazine, cisplatin, doxorubicin, carboplatin, taxane, paclitaxel, docetaxel, 5-fluorouraci, vincristine, methotrexate, dactinomycin, bleomycin, mercaptopurine). OUTCOMES The ovarian microenvironment shows great changes during chemotherapy, inducing extracellular matrix deposition and stromal fibrosis, angiogenesis disorders, immune microenvironment disturbance, oxidative stress imbalances, ovarian stem cell exhaustion, and cell senescence, thereby lowering the quantity and quality of ovarian follicles. Several methods targeting the ovarian microenvironment have been adopted to prevent and treat CAOD, such as stem cell therapy and the use of free radical scavengers, senolytherapies, immunomodulators, and proangiogenic factors. WIDER IMPLICATIONS Ovarian function is determined by its 'seeds' (follicles) and 'soil' (ovarian microenvironment). The ovarian microenvironment has been reported to play a vital role in CAOD and targeting the ovarian microenvironment may present potential therapeutic approaches for CAOD. However, the relation between the ovarian microenvironment, its regulatory networks, and CAOD needs to be further studied. A better understanding of these issues could be helpful in explaining the pathogenesis of CAOD and creating innovative strategies for counteracting the effects exerted on ovarian function. Our aim is that this narrative review of CAOD will stimulate more research in this important field. REGISTRATION NUMBER Not applicable.
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Affiliation(s)
- Yican Guo
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Liru Xue
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Weicheng Tang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Jiaqiang Xiong
- Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Dan Chen
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Yun Dai
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Chuqing Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Simin Wei
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Jun Dai
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Meng Wu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- National Clinical Research Center for Obstetrical and Gynecological Diseases, Wuhan, Hubei, China
- Key Laboratory of Cancer Invasion and Metastasis, Ministry of Education, Wuhan, Hubei, China
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Jia W, Yuan J, Zhang J, Li S, Lin W, Cheng B. Bioactive sphingolipids as emerging targets for signal transduction in cancer development. Biochim Biophys Acta Rev Cancer 2024; 1879:189176. [PMID: 39233263 DOI: 10.1016/j.bbcan.2024.189176] [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: 06/06/2024] [Revised: 08/28/2024] [Accepted: 08/28/2024] [Indexed: 09/06/2024]
Abstract
Sphingolipids, crucial components of cellular membranes, play a vital role in maintaining cellular structure and signaling integrity. Disruptions in sphingolipid metabolism are increasingly implicated in cancer development. Key bioactive sphingolipids, such as ceramides, sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glycosphingolipids, profoundly impact tumor biology. They influence the behavior of tumor cells, stromal cells, and immune cells, affecting tumor aggressiveness, angiogenesis, immune modulation, and extracellular matrix remodeling. Furthermore, abnormal expression of sphingolipids and their metabolizing enzymes modulates the secretion of tumor-derived extracellular vesicles (TDEs), which are key players in creating an immunosuppressive tumor microenvironment, remodeling the extracellular matrix, and facilitating oncogenic signaling within in situ tumors and distant pre-metastatic niches (PMNs). Understanding the role of sphingolipids in the biogenesis of tumor-derived extracellular vesicles (TDEs) and their bioactive contents can pave the way for new biomarkers in cancer diagnosis and prognosis, ultimately enhancing comprehensive tumor treatment strategies.
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Affiliation(s)
- Wentao Jia
- Department of General Practice, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai 200043, China
| | - Jiaying Yuan
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China
| | - Jinbo Zhang
- Department of Pharmacy, Tianjin Rehabilitation and Recuperation Center, Joint Logistics Support Force, Tianjin 300000, China
| | - Shu Li
- Department of Gastroenterology, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201900, China
| | - Wanfu Lin
- Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai 200043, China.
| | - Binbin Cheng
- Oncology Department of Traditional Chinese Medicine, The First Affiliated Hospital of Naval Medical University, Shanghai 200433, China; Faculty of Traditional Chinese Medicine, Naval Medical University, Shanghai 200043, China.
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SenthilKumar G, Zirgibel Z, Cohen KE, Katunaric B, Jobe AM, Shult CG, Limpert RH, Freed JK. Ying and Yang of Ceramide in the Vascular Endothelium. Arterioscler Thromb Vasc Biol 2024; 44:1725-1736. [PMID: 38899471 PMCID: PMC11269027 DOI: 10.1161/atvbaha.124.321158] [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: 06/21/2024]
Abstract
Ceramides, a group of biologically active sphingolipids, have been described as the new cholesterol given strong evidence linking high plasma ceramide with endothelial damage, risk for early adverse cardiovascular events, and development of cardiometabolic disease. This relationship has sparked great interest in investigating therapeutic targets with the goal of suppressing ceramide formation. However, the growing data challenge this paradigm of ceramide as solely eliciting detrimental effects to the cardiovascular system. Studies show that ceramides are necessary for maintaining proper endothelial redox states, mechanosensation, and membrane integrity. Recent work in preclinical models and isolated human microvessels highlights that the loss of ceramide formation can in fact propagate vascular endothelial dysfunction. Here, we delve into these conflicting findings to evaluate how ceramide may be capable of exerting both beneficial and damaging effects within the vascular endothelium. We propose a unifying theory that while basal levels of ceramide in response to physiological stimuli are required for the production of vasoprotective metabolites such as S1P (sphingosine-1-phosphate), the chronic accumulation of ceramide can promote activation of pro-oxidative stress pathways in endothelial cells. Clinically, the evidence discussed here highlights the potential challenges associated with therapeutic suppression of ceramide formation as a means of reducing cardiovascular disease risk.
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Affiliation(s)
- Gopika SenthilKumar
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee WI
- Department of Physiology, Medical College of Wisconsin, Milwaukee WI
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee WI
| | - Zachary Zirgibel
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee WI
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee WI
| | - Katie E. Cohen
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee WI
- Division of Cardiovascular Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee WI
| | - Boran Katunaric
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee WI
- Department of Physiology, Medical College of Wisconsin, Milwaukee WI
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee WI
| | - Alyssa M. Jobe
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee WI
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee WI
| | - Carolyn G. Shult
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee WI
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee WI
| | - Rachel H. Limpert
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee WI
- Department of Physiology, Medical College of Wisconsin, Milwaukee WI
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee WI
| | - Julie K. Freed
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee WI
- Department of Physiology, Medical College of Wisconsin, Milwaukee WI
- Cardiovascular Center, Medical College of Wisconsin, Milwaukee WI
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Seal A, Hughes M, Wei F, Pugazhendhi AS, Ngo C, Ruiz J, Schwartzman JD, Coathup MJ. Sphingolipid-Induced Bone Regulation and Its Emerging Role in Dysfunction Due to Disease and Infection. Int J Mol Sci 2024; 25:3024. [PMID: 38474268 PMCID: PMC10932382 DOI: 10.3390/ijms25053024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/02/2024] [Accepted: 03/04/2024] [Indexed: 03/14/2024] Open
Abstract
The human skeleton is a metabolically active system that is constantly regenerating via the tightly regulated and highly coordinated processes of bone resorption and formation. Emerging evidence reveals fascinating new insights into the role of sphingolipids, including sphingomyelin, sphingosine, ceramide, and sphingosine-1-phosphate, in bone homeostasis. Sphingolipids are a major class of highly bioactive lipids able to activate distinct protein targets including, lipases, phosphatases, and kinases, thereby conferring distinct cellular functions beyond energy metabolism. Lipids are known to contribute to the progression of chronic inflammation, and notably, an increase in bone marrow adiposity parallel to elevated bone loss is observed in most pathological bone conditions, including aging, rheumatoid arthritis, osteoarthritis, and osteomyelitis. Of the numerous classes of lipids that form, sphingolipids are considered among the most deleterious. This review highlights the important primary role of sphingolipids in bone homeostasis and how dysregulation of these bioactive metabolites appears central to many chronic bone-related diseases. Further, their contribution to the invasion, virulence, and colonization of both viral and bacterial host cell infections is also discussed. Many unmet clinical needs remain, and data to date suggest the future use of sphingolipid-targeted therapy to regulate bone dysfunction due to a variety of diseases or infection are highly promising. However, deciphering the biochemical and molecular mechanisms of this diverse and extremely complex sphingolipidome, both in terms of bone health and disease, is considered the next frontier in the field.
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Affiliation(s)
- Anouska Seal
- Biionix Cluster, University of Central Florida, Orlando, FL 32827, USA; (A.S.); (F.W.); (A.S.P.); (C.N.)
| | - Megan Hughes
- School of Biosciences, Cardiff University, Cardiff CF10 3AT, UK;
| | - Fei Wei
- Biionix Cluster, University of Central Florida, Orlando, FL 32827, USA; (A.S.); (F.W.); (A.S.P.); (C.N.)
- College of Medicine, University of Central Florida, Orlando, FL 32827, USA (J.D.S.)
| | - Abinaya S. Pugazhendhi
- Biionix Cluster, University of Central Florida, Orlando, FL 32827, USA; (A.S.); (F.W.); (A.S.P.); (C.N.)
- College of Medicine, University of Central Florida, Orlando, FL 32827, USA (J.D.S.)
| | - Christopher Ngo
- Biionix Cluster, University of Central Florida, Orlando, FL 32827, USA; (A.S.); (F.W.); (A.S.P.); (C.N.)
- College of Medicine, University of Central Florida, Orlando, FL 32827, USA (J.D.S.)
| | - Jonathan Ruiz
- College of Medicine, University of Central Florida, Orlando, FL 32827, USA (J.D.S.)
| | | | - Melanie J. Coathup
- Biionix Cluster, University of Central Florida, Orlando, FL 32827, USA; (A.S.); (F.W.); (A.S.P.); (C.N.)
- College of Medicine, University of Central Florida, Orlando, FL 32827, USA (J.D.S.)
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Lindoso RS, Collino F, Kasai-Brunswick TH, Costa MR, Verdoorn KS, Einicker-Lamas M, Vieira-Beiral HJ, Wessely O, Vieyra A. Resident Stem Cells in Kidney Tissue. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:159-203. [DOI: 10.1016/b978-0-443-15289-4.00009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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7
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Ortiz Wilczyñski JM, Mena HA, Ledesma MM, Olexen CM, Podaza E, Schattner M, Negrotto S, Errasti AE, Carrera Silva EA. The synthetic phospholipid C8-C1P determines pro-angiogenic and pro-reparative features in human macrophages restraining the proinflammatory M1-like phenotype. Front Immunol 2023; 14:1162671. [PMID: 37398671 PMCID: PMC10311553 DOI: 10.3389/fimmu.2023.1162671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/31/2023] [Indexed: 07/04/2023] Open
Abstract
Monocytes (Mo) are highly plastic myeloid cells that differentiate into macrophages after extravasation, playing a pivotal role in the resolution of inflammation and regeneration of injured tissues. Wound-infiltrated monocytes/macrophages are more pro-inflammatory at early time points, while showing anti-inflammatory/pro-reparative phenotypes at later phases, with highly dynamic switching depending on the wound environment. Chronic wounds are often arrested in the inflammatory phase with hampered inflammatory/repair phenotype transition. Promoting the tissue repair program switching represents a promising strategy to revert chronic inflammatory wounds, one of the major public health loads. We found that the synthetic lipid C8-C1P primes human CD14+ monocytes, restraining the inflammatory activation markers (HLA-DR, CD44, and CD80) and IL-6 when challenged with LPS, and preventing apoptosis by inducing BCL-2. We also observed increased pseudo-tubule formation of human endothelial-colony-forming cells (ECFCs) when stimulated with the C1P-macrophages secretome. Moreover, C8-C1P-primed monocytes skew differentiation toward pro-resolutive-like macrophages, even in the presence of inflammatory PAMPs and DAMPs by increasing anti-inflammatory and pro-angiogenic gene expression patterns. All these results indicate that C8-C1P could restrain M1 skewing and promote the program of tissue repair and pro-angiogenic macrophage.
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Affiliation(s)
- Juan Manuel Ortiz Wilczyñski
- Institute of Experimental Medicine, National Scientific and Technological Research Council - National Academy of Medicine (IMEX-CONICET-ANM), Buenos Aires, Argentina
| | - Hebe Agustina Mena
- Institute of Experimental Medicine, National Scientific and Technological Research Council - National Academy of Medicine (IMEX-CONICET-ANM), Buenos Aires, Argentina
| | - Martin Manuel Ledesma
- Institute of Experimental Medicine, National Scientific and Technological Research Council - National Academy of Medicine (IMEX-CONICET-ANM), Buenos Aires, Argentina
| | - Cinthia Mariel Olexen
- Institute of Experimental Medicine, National Scientific and Technological Research Council - National Academy of Medicine (IMEX-CONICET-ANM), Buenos Aires, Argentina
- Institute of Pharmacology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Enrique Podaza
- Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, United States
| | - Mirta Schattner
- Institute of Experimental Medicine, National Scientific and Technological Research Council - National Academy of Medicine (IMEX-CONICET-ANM), Buenos Aires, Argentina
| | - Soledad Negrotto
- Institute of Experimental Medicine, National Scientific and Technological Research Council - National Academy of Medicine (IMEX-CONICET-ANM), Buenos Aires, Argentina
| | - Andrea Emilse Errasti
- Institute of Pharmacology, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Eugenio Antonio Carrera Silva
- Institute of Experimental Medicine, National Scientific and Technological Research Council - National Academy of Medicine (IMEX-CONICET-ANM), Buenos Aires, Argentina
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Raza Y, Atallah J, Luberto C. Advancements on the Multifaceted Roles of Sphingolipids in Hematological Malignancies. Int J Mol Sci 2022; 23:12745. [PMID: 36361536 PMCID: PMC9654982 DOI: 10.3390/ijms232112745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/07/2022] [Accepted: 10/17/2022] [Indexed: 09/19/2023] Open
Abstract
Dysregulation of sphingolipid metabolism plays a complex role in hematological malignancies, beginning with the first historical link between sphingolipids and apoptosis discovered in HL-60 leukemic cells. Numerous manuscripts have reviewed the field including the early discoveries that jumpstarted the studies. Many studies discussed here support a role for sphingolipids, such as ceramide, in combinatorial therapeutic regimens to enhance anti-leukemic effects and reduce resistance to standard therapies. Additionally, inhibitors of specific nodes of the sphingolipid pathway, such as sphingosine kinase inhibitors, significantly reduce leukemic cell survival in various types of leukemias. Acid ceramidase inhibitors have also shown promising results in acute myeloid leukemia. As the field moves rapidly, here we aim to expand the body of literature discussed in previously published reviews by focusing on advances reported in the latter part of the last decade.
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Affiliation(s)
- Yasharah Raza
- Department of Pharmacological Sciences, Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, NY 11794, USA
- Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
| | - Jane Atallah
- Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
| | - Chiara Luberto
- Stony Brook Cancer Center, Stony Brook University Hospital, Stony Brook, NY 11794, USA
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
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9
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Simón MV, Vera MS, Tenconi PE, Soto T, Prado Spalm FH, Torlaschi C, Mateos MV, Rotstein NP. Sphingosine-1-phosphate and ceramide-1-phosphate promote migration, pro-inflammatory and pro-fibrotic responses in retinal pigment epithelium cells. Exp Eye Res 2022; 224:109222. [PMID: 36041511 DOI: 10.1016/j.exer.2022.109222] [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: 06/01/2022] [Revised: 08/04/2022] [Accepted: 08/16/2022] [Indexed: 11/18/2022]
Abstract
Retinal pigment epithelium (RPE) cells, essential for preserving retina homeostasis, also contribute to the development of retina proliferative diseases, through their exacerbated migration, epithelial to mesenchymal transition (EMT) and inflammatory response. Uncovering the mechanisms inducing these changes is crucial for designing effective treatments for these pathologies. Sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) are bioactive sphingolipids that promote migration and inflammation in several cell types; we recently established that they stimulate the migration of retina Müller glial cells (Simón et al., 2015; Vera et al., 2021). We here analyzed whether S1P and C1P regulate migration, inflammation and EMT in RPE cells. We cultured two human RPE cell lines, ARPE-19 and D407 cells, and supplemented them with either 5 μM S1P or 10 μM C1P, or their vehicles, for 24 h. Analysis of cell migration by the scratch wound assay showed that S1P addition significantly enhanced migration in both cell lines. Pre-treatment with W146 and BML-241, antagonists for S1P receptor 1 (S1P1) and 3 (S1P3), respectively, blocked exogenous S1P-induced migration. Inhibiting sphingosine kinase 1 (SphK1), the enzyme involved in S1P synthesis, significantly reduced cell migration and exogenous S1P only partially restored it. Addition of C1P markedly stimulated cell migration. Whereas inhibiting C1P synthesis did not affect C1P-induced migration, inhibiting S1P synthesis strikingly decreased it; noteworthy, addition of C1P promoted the transcription of SphK1. These results suggest that S1P and C1P stimulate RPE cell migration and their effect requires S1P endogenous synthesis. Both S1P and C1P increase the transcription of pro-inflammatory cytokines IL-6 and IL-8, and of EMT marker α-smooth muscle actin (α-SMA) in ARPE-19 cells. Collectively, our results suggest new roles for S1P and C1P in the regulation of RPE cell migration and inflammation; since the deregulation of sphingolipid metabolism is involved in several proliferative retinopathies, targeting their metabolism might provide new tools for treating these pathologies.
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Affiliation(s)
- M Victoria Simón
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina.
| | - Marcela S Vera
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Paula E Tenconi
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Tamara Soto
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Facundo H Prado Spalm
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Camila Torlaschi
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Melina V Mateos
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Nora P Rotstein
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina.
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10
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Ouro A, Correa-Paz C, Maqueda E, Custodia A, Aramburu-Núñez M, Romaus-Sanjurjo D, Posado-Fernández A, Candamo-Lourido M, Alonso-Alonso ML, Hervella P, Iglesias-Rey R, Castillo J, Campos F, Sobrino T. Involvement of Ceramide Metabolism in Cerebral Ischemia. Front Mol Biosci 2022; 9:864618. [PMID: 35531465 PMCID: PMC9067562 DOI: 10.3389/fmolb.2022.864618] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/11/2022] [Indexed: 12/12/2022] Open
Abstract
Ischemic stroke, caused by the interruption of blood flow to the brain and subsequent neuronal death, represents one of the main causes of disability in worldwide. Although reperfusion therapies have shown efficacy in a limited number of patients with acute ischemic stroke, neuroprotective drugs and recovery strategies have been widely assessed, but none of them have been successful in clinical practice. Therefore, the search for new therapeutic approaches is still necessary. Sphingolipids consist of a family of lipidic molecules with both structural and cell signaling functions. Regulation of sphingolipid metabolism is crucial for cell fate and homeostasis in the body. Different works have emphasized the implication of its metabolism in different pathologies, such as diabetes, cancer, neurodegeneration, or atherosclerosis. Other studies have shown its implication in the risk of suffering a stroke and its progression. This review will highlight the implications of sphingolipid metabolism enzymes in acute ischemic stroke.
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Affiliation(s)
- Alberto Ouro
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Clara Correa-Paz
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Elena Maqueda
- Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Antía Custodia
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Marta Aramburu-Núñez
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Daniel Romaus-Sanjurjo
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Adrián Posado-Fernández
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - María Candamo-Lourido
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Maria Luz Alonso-Alonso
- Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Pablo Hervella
- Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Ramón Iglesias-Rey
- Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - José Castillo
- Neuroimaging and Biotechnology Laboratory (NOBEL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Francisco Campos
- Translational Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Tomás Sobrino
- NeuroAging Group (NEURAL), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
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11
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Implication of Ceramide Kinase/C1P in Cancer Development and Progression. Cancers (Basel) 2022; 14:cancers14010227. [PMID: 35008391 PMCID: PMC8750078 DOI: 10.3390/cancers14010227] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 12/28/2022] Open
Abstract
Cancer cells rewire their metabolic programs to favor biological processes that promote cell survival, proliferation, and dissemination. Among this relevant reprogramming, sphingolipid metabolism provides metabolites that can favor or oppose these hallmarks of cancer. The sphingolipid ceramide 1-phosphate (C1P) and the enzyme responsible for its biosynthesis, ceramide kinase (CERK), are well established regulators of cell growth and survival in normal, as well as malignant cells through stress-regulated signaling pathways. This metabolite also promotes cell survival, which has been associated with the feedback regulation of other antitumoral sphingolipids or second messengers. C1P also regulates cancer cell invasion and migration of different types of cancer, including lung, breast, pancreas, prostate, or leukemia cells. More recently, CERK and C1P have been implicated in the control of inflammatory responses. The present review provides an updated view on the important role of CERK/C1P in the regulation of cancer cell growth, survival, and dissemination.
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12
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Hua T, Bao Q, He X, Cai W, He J. Lipidomics Revealed Alteration of Sphingolipid Metabolism During the Reparative Phase After Myocardial Infarction Injury. Front Physiol 2021; 12:663480. [PMID: 33776806 PMCID: PMC7994894 DOI: 10.3389/fphys.2021.663480] [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: 02/03/2021] [Accepted: 02/23/2021] [Indexed: 01/10/2023] Open
Abstract
Aberrant sphingolipid metabolism contributes to cardiac pathophysiology. Emerging evidence found that an increased level of ceramide during the inflammatory phase of post-myocardial infarction (MI) served as a biomarker and was associated with cardiac dysfunction. However, the alternation of the sphingolipid profile during the reparative phase after MI is still not fully understood. Using a mouse model of the left anterior descending ligation that leads to MI, we performed metabolomics studies to assess the alternations of both plasma and myocardial sphingolipid profiles during the reparative phase post-MI. A total number of 193 sphingolipid metabolites were detected. Myocardial sphingolipids but not plasma sphingolipids showed marked change after MI injury. Ceramide-1-phosphates, which were accumulated after MI, contributed highly to the difference in sphingolipid profiles between groups. Consistently, the expression of ceramide kinase, which phosphorylates ceramides to generate ceramide-1-phosphates, was upregulated in heart tissue after MI injury. Our findings revealed the altering sphingolipid metabolism during the reparative phase post-MI and highlighted the potential role of ceramide kinase/ceramide-1-phosphate in ischemic heart disease.
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Affiliation(s)
- Tong Hua
- Tianjin Key Laboratory of Metabolic Diseases, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Qiankun Bao
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Xue He
- Tianjin Key Laboratory of Metabolic Diseases, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Wenbin Cai
- Tianjin Key Laboratory of Metabolic Diseases, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
| | - Jinlong He
- Tianjin Key Laboratory of Metabolic Diseases, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China
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13
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Regulation of cell growth, survival and migration by ceramide 1-phosphate - implications in lung cancer progression and inflammation. Cell Signal 2021; 83:109980. [PMID: 33727076 DOI: 10.1016/j.cellsig.2021.109980] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 01/10/2023]
Abstract
Ceramide 1-phosphate (C1P) is a bioactive sphingolipid that is implicated in the regulation of vital cellular functions and plays key roles in a number of inflammation-associated pathologies. C1P was first described as mitogenic for fibroblasts and macrophages and was later found to promote cell survival in different cell types. The mechanisms involved in the mitogenic actions of C1P include activation of MEK/ERK1-2, PI3K/Akt/mTOR, or PKC-α, whereas promotion of cell survival required a substantial reduction of ceramide levels through inhibition of serine palmitoyl transferase or sphingomyelinase activities. C1P and ceramide kinase (CerK), the enzyme responsible for its biosynthesis in mammalian cells, play key roles in tumor promotion and dissemination. CerK-derived C1P can be secreted to the extracellular milieu by different cell types and is also present in extracellular vesicles. In this context, whilst cell proliferation is regulated by intracellularly generated C1P, stimulation of cell migration/invasion requires the intervention of exogenous C1P. Regarding inflammation, C1P was first described as pro-inflammatory in a variety of cell types. However, cigarette smoke- or lipopolysaccharide-induced lung inflammation in mouse or human cells was overcome by pretreatment with natural or synthetic C1P analogs. Both acute and chronic lung inflammation, and the development of lung emphysema were substantially reduced by exogenous C1P applications, pointing to an anti-inflammatory action of C1P in the lungs. The molecular mechanisms involved in the regulation of cell growth, survival and migration with especial emphasis in the control of lung cancer biology are discussed.
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14
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Role of bioactive sphingolipids in physiology and pathology. Essays Biochem 2021; 64:579-589. [PMID: 32579188 DOI: 10.1042/ebc20190091] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 12/27/2022]
Abstract
Sphingolipids are a class of complex lipids containing a backbone of sphingoid bases, namely the organic aliphatic amino alcohol sphingosine (Sph), that are essential constituents of eukaryotic cells. They were first described as major components of cell membrane architecture, but it is now well established that some sphingolipids are bioactive and can regulate key biological functions. These include cell growth and survival, cell differentiation, angiogenesis, autophagy, cell migration, or organogenesis. Furthermore, some bioactive sphingolipids are implicated in pathological processes including inflammation-associated illnesses such as atherosclerosis, rheumatoid arthritis, inflammatory bowel disease (namely Crohn's disease and ulcerative colitis), type II diabetes, obesity, and cancer. A major sphingolipid metabolite is ceramide, which is the core of sphingolipid metabolism and can act as second messenger, especially when it is produced at the plasma membrane of cells. Ceramides promote cell cycle arrest and apoptosis. However, ceramide 1-phosphate (C1P), the product of ceramide kinase (CerK), and Sph 1-phosphate (S1P), which is generated by the action of Sph kinases (SphK), stimulate cell proliferation and inhibit apoptosis. Recently, C1P has been implicated in the spontaneous migration of cells from some types of cancer, and can enhance cell migration/invasion of malignant cells through interaction with a Gi protein-coupled receptor. In addition, CerK and SphK are implicated in inflammatory responses, some of which are associated with cancer progression and metastasis. Hence, targeting these sphingolipid kinases to inhibit C1P or S1P production, or blockade of their receptors might contribute to the development of novel therapeutic strategies to reduce metabolic alterations and disease.
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15
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Vera MS, Simón MV, Prado Spalm FH, Ayala-Peña VB, German OL, Politi LE, Santiago Valtierra FX, Rotstein NP. Ceramide-1-phosphate promotes the migration of retina Müller glial cells. Exp Eye Res 2020; 202:108359. [PMID: 33197453 DOI: 10.1016/j.exer.2020.108359] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/30/2020] [Accepted: 11/07/2020] [Indexed: 12/13/2022]
Abstract
Müller glial cells, the major glial cell type in the retina, are activated by most retina injuries, leading to an increased proliferation and migration that contributes to visual dysfunction. The molecular cues involved in these processes are still ill defined. We demonstrated that sphingosine-1-phosphate (S1P), a bioactive sphingolipid, promotes glial migration. We now investigated whether ceramide-1-phosphate (C1P), also a bioactive sphingolipid, was involved in Müller glial cell migration. We evaluated cell migration in primary Müller glial cultures, prepared from newborn rat retinas, by the scratch wound assay. Addition of either 10 μM C8-ceramide-1-phosphate (C8-C1P) or 5 μM C16-C1P (a long chain, natural C1P) stimulated glial migration. Inhibiting PI3K almost completely blocked C8-C1P-elicited migration whereas inhibition of ERK1-2/MAPK pathway diminished it and p38MAPK inhibition did not affect it. Pre-treatment with a cytoplasmic phospholipase A2 (cPLA2) inhibitor markedly reduced C8-C1P-induced migration. Inhibiting ceramide kinase (CerK), the enzyme catalyzing C1P synthesis, partially decreased glial migration. Combined addition of S1P and C8-C1P promoted glial migration to the same extent as when they were added separately, suggesting they converge on their downstream signaling to stimulate Müller glia migration. These results suggest that C1P addition stimulated migration of glial Müller cells, promoting the activation of cPLA2, and the PI3K and ERK/MAPK pathways. They also suggest that CerK-dependent C1P synthesis was one of the factors contributing to glial migration, thus uncovering a novel role for C1P in controlling glial motility.
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Affiliation(s)
- Marcela S Vera
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - M Victoria Simón
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Facundo H Prado Spalm
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Victoria B Ayala-Peña
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - O Lorena German
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Luis E Politi
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Florencia X Santiago Valtierra
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina
| | - Nora P Rotstein
- Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Dept. of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur (UNS) and National Research Council of Argentina (CONICET), Bahía Blanca, Buenos Aires, Argentina.
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16
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The Peripherin Gene Regulates the Migration of Bone Marrow Mesenchymal Stem Cells in Wuzhishan Mini Pigs. Stem Cells Int 2020; 2020:8856388. [PMID: 33101422 PMCID: PMC7576346 DOI: 10.1155/2020/8856388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/04/2020] [Accepted: 09/05/2020] [Indexed: 11/18/2022] Open
Abstract
Increasing the migratory capacity of the implanted mesenchymal stem cells (MSCs) is a major challenge in developing successful cell transplantation therapies. Nevertheless, the regulatory factors involved in the migration of BMMSCs remain largely unknown. In this study, we studied the role of the peripherin (PRPH) gene in regulating the ability of Wuzhishan mini pig (WZSP) BMMSCs to migrate in vitro. Four different shRNA vectors directed against PRPH were designed and transfected into BMMSCs. The vector with the best interference effect was chosen to be used in the following experiments. The expression level of PRPH in BMMSCs was determined by quantitative real-time PCR and western blot analysis. The migration capacity of the BMMSCs was estimated using a scratch assay, a transwell in vitro migration model assay, and filamentous actin staining. The results showed that shRNA-mediated knockdown of the expression of the PRPH gene in BMMSCs reduced the ability of these cells to migrate. Overall, these results illustrate that the PRPH gene regulates the migration of BMMSCs in the WZSP.
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17
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Podbielska M, Szulc ZM, Ariga T, Pokryszko-Dragan A, Fortuna W, Bilinska M, Podemski R, Jaskiewicz E, Kurowska E, Yu RK, Hogan EL. Distinctive sphingolipid patterns in chronic multiple sclerosis lesions. J Lipid Res 2020; 61:1464-1479. [PMID: 32769146 PMCID: PMC7604719 DOI: 10.1194/jlr.ra120001022] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Multiple sclerosis (MS) is a CNS disease characterized by immune-mediated demyelination and progressive axonal loss. MS-related CNS damage and its clinical course have two main phases: active and inactive/progressive. Reliable biomarkers are being sought to allow identification of MS pathomechanisms and prediction of its course. The purpose of this study was to identify sphingolipid (SL) species as candidate biomarkers of inflammatory and neurodegenerative processes underlying MS pathology. We performed sphingolipidomic analysis by HPLC-tandem mass spectrometry to determine the lipid profiles in post mortem specimens from the normal-appearing white matter (NAWM) of the normal CNS (nCNS) from subjects with chronic MS (active and inactive lesions) as well as from patients with other neurological diseases. Distinctive SL modification patterns occurred in specimens from MS patients with chronic inactive plaques with respect to NAWM from the nCNS and active MS (Ac-MS) lesions. Chronic inactive MS (In-MS) lesions were characterized by decreased levels of dihydroceramide (dhCer), ceramide (Cer), and SM subspecies, whereas levels of hexosylceramide and Cer 1-phosphate (C1P) subspecies were significantly increased in comparison to NAWM of the nCNS as well as Ac-MS plaques. In contrast, Ac-MS lesions were characterized by a significant increase of major dhCer subspecies in comparison to NAWM of the nCNS. These results suggest the existence of different SL metabolic pathways in the active versus inactive phase within progressive stages of MS. Moreover, they suggest that C1P could be a new biomarker of the In-MS progressive phase, and its detection may help to develop future prognostic and therapeutic strategies for the disease.
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Affiliation(s)
- Maria Podbielska
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.,Laboratory of Microbiome Immunobiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Zdzislaw M Szulc
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Toshio Ariga
- Department of Neuroscience and Regenerative Medicine, Augusta University, Medical College of Georgia, Augusta, GA 30912, USA
| | | | - Wojciech Fortuna
- Department of Neurosurgery, Wroclaw Medical University, Wroclaw, Poland.,Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | | | - Ryszard Podemski
- Department of Neurology, Wroclaw Medical University, Wroclaw, Poland
| | - Ewa Jaskiewicz
- Laboratory of Glycobiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Ewa Kurowska
- Laboratory of Microbiome Immunobiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Robert K Yu
- Department of Neuroscience and Regenerative Medicine, Augusta University, Medical College of Georgia, Augusta, GA 30912, USA
| | - Edward L Hogan
- Department of Neurology, Medical University of South Carolina, Charleston, SC, USA
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18
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Tomizawa S, Tamori M, Tanaka A, Utsumi N, Sato H, Hatakeyama H, Hisaka A, Kohama T, Yamagata K, Honda T, Nakamura H, Murayama T. Inhibitory effects of ceramide kinase on Rac1 activation, lamellipodium formation, cell migration, and metastasis of A549 lung cancer cells. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158675. [PMID: 32112978 DOI: 10.1016/j.bbalip.2020.158675] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 01/30/2020] [Accepted: 02/22/2020] [Indexed: 01/01/2023]
Abstract
Ceramide kinase (CerK) phosphorylates ceramide to ceramide-1-phosphate (C1P), a bioactive sphingolipid. Since the mechanisms responsible for regulating the proliferation and migration/metastasis of cancer cells by the CerK/C1P pathway remain unclear, we conducted the present study. The knockdown of CerK in A549 lung and MCF-7 breast cancer cells (shCerK cells) increased the formation of lamellipodia, which are membrane protrusions coupled with cell migration. Mouse embryonic fibroblasts prepared from CerK-null mice also showed an enhanced formation of lamellipodia. The overexpression of CerK inhibited lamellipodium formation in A549 cells. The knockdown of CerK increased the number of cells having lamellipodia with Rac1 and the levels of active Rac1-GTP form, whereas the overexpression of CerK decreased them. CerK was located in lamellipodia after the epidermal growth factor treatment, indicating that CerK functioned there to inhibit Rac1. The migration of A549 cells was negatively regulated by CerK. An intravenous injection of A549-shCerK cells into nude mice resulted in markedly stronger metastatic responses in the lungs than an injection of control cells. The in vitro growth of A549 cells and in vivo expansion after the injection into mouse flanks were not affected by the CerK knockdown. These results suggest that the activation of CerK/C1P pathway has inhibitory roles on lamellipodium formation, migration, and metastasis of A549 lung cancer cells.
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Affiliation(s)
- Satoshi Tomizawa
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Mizuki Tamori
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Ai Tanaka
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Naoya Utsumi
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Hiromi Sato
- Laboratory of Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Hiroto Hatakeyama
- Laboratory of Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Akihiro Hisaka
- Laboratory of Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Takafumi Kohama
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan; Research Coordination Group, Research Management Department, Daiichi Sankyo RD Novare Co., Ltd., 1016-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan
| | - Kazuyuki Yamagata
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Takuya Honda
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
| | - Hiroyuki Nakamura
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
| | - Toshihiko Murayama
- Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
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19
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Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt. Int J Mol Sci 2020; 21:ijms21041396. [PMID: 32092937 PMCID: PMC7073039 DOI: 10.3390/ijms21041396] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/28/2020] [Accepted: 02/12/2020] [Indexed: 01/04/2023] Open
Abstract
Ceramide kinase (CerK) is a lipid kinase that converts the proapoptotic ceramide to ceramide 1-phosphate, which has been proposed to have pro-malignant properties and regulate cell responses such as proliferation, migration, and inflammation. We used the parental human breast cancer cell line MDA-MB-231 and two single cell progenies derived from lung and bone metastasis upon injection of the parental cells into immuno-deficient mice. The lung and the bone metastatic cell lines showed a marked upregulation of CerK mRNA and activity when compared to the parental cell line. The metastatic cells also had increased migratory and invasive activity, which was dose-dependently reduced by the selective CerK inhibitor NVP-231. A similar reduction of migration was seen when CerK was stably downregulated with small hairpin RNA (shRNA). Conversely, overexpression of CerK in parental MDA-MB-231 cells enhanced migration, and this effect was also observed in the non-metastatic cell line MCF7 upon CerK overexpression. On the molecular level, CerK overexpression increased the activation of protein kinase Akt. The increased migration of CerK overexpressing cells was mitigated by the CerK inhibitor NVP-231, by inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway and the Rho kinase, but not by inhibition of the classical extracellular signal-regulated kinase (ERK) pathway. Altogether, our data demonstrate for the first time that CerK promotes migration and invasion of metastatic breast cancer cells and that targeting of CerK has potential to counteract metastasis in breast cancer.
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20
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Presa N, Gomez-Larrauri A, Dominguez-Herrera A, Trueba M, Gomez-Muñoz A. Novel signaling aspects of ceramide 1-phosphate. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158630. [PMID: 31958571 DOI: 10.1016/j.bbalip.2020.158630] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 01/09/2020] [Accepted: 01/11/2020] [Indexed: 12/12/2022]
Abstract
The bioactive sphingolipid ceramide 1-phosphate (C1P) regulates key physiologic cell functions and is implicated in a number of metabolic alterations and pathological processes. Initial studies using different types of fibroblasts and monocytes/macrophages revealed that C1P was mitogenic and that it promoted cell survival through inhibition of apoptosis. Subsequent studies implicated C1P in inflammatory responses with a specific role as pro-inflammatory agent. Specifically, C1P potently stimulated cytosolic phospholipase A2 (cPLA2) resulting in elevation of arachidonic acid and pro-inflammatory eicosanoid levels. However, increasing experimental evidence suggests that C1P can also exert anti-inflammatory actions in some cell types and tissues. Specifically, it has been demonstrated that C1P inhibits the release of pro-inflammatory cytokines and blocks activation of the pro-inflammatory transcription factor NF-κB in some cell types. Moreover, C1P was shown to increase the release of anti-inflammatory interleukin-10 in macrophages, and to overcome airway inflammation and reduce lung emphysema in vivo. Noteworthy, C1P stimulated cell migration, an action that is associated with diverse physiological cell functions, as well as with inflammatory responses and tumor dissemination. More recently, ceramide kinase (CerK), the enzyme that produces C1P in mammalian cells, has been shown to be upregulated during differentiation of pre-adipocytes into mature adipocytes, and that exogenous C1P, acting through a putative Gi protein-coupled receptor, negatively regulates adipogenesis. Although the latter actions seem to be contradictory, it is plausible that exogenous C1P may balance the adipogenic effects of intracellularly generated (CerK-derived) C1P in adipose tissue. The present review highlights novel signaling aspects of C1P and its impact in the regulation of cell growth and survival, inflammation and tumor dissemination.
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Affiliation(s)
- Natalia Presa
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Vizcaya, Spain
| | - Ana Gomez-Larrauri
- Department of Pneumology, Cruces University Hospital, Barakaldo, Vizcaya, Spain
| | - Asier Dominguez-Herrera
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Vizcaya, Spain
| | - Miguel Trueba
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Vizcaya, Spain
| | - Antonio Gomez-Muñoz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Vizcaya, Spain.
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Mallela SK, Mitrofanova A, Merscher S, Fornoni A. Regulation of the amount of ceramide-1-phosphate synthesized in differentiated human podocytes. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:158517. [PMID: 31487557 PMCID: PMC6832884 DOI: 10.1016/j.bbalip.2019.158517] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 08/09/2019] [Accepted: 08/26/2019] [Indexed: 12/14/2022]
Abstract
Sphingolipids have important functions as structural components of cells but they also function as signaling molecules regulating different cellular processes such as apoptosis, cell proliferation, cell migration, cell division and inflammation. Hence, a tight regulation of the sphingolipid homeostasis is essential to maintain proper cellular functions. Mammalian ORMDL proteins are orthologues of the yeast ORM1/2 proteins, which regulate ceramide synthesis in yeast. ORMDL proteins inhibit serine palmitoyltransferase (SPT), the enzyme regulating a rate-limiting step of the sphingolipid pathway to control the levels of ceramides and other sphingolipids. Sphingomyelinase phosphodiesterase like 3b (SMPDL3b) is a glycosylphosphatidylinositol (GPI) anchored protein in the plasma membrane (PM) and determines membrane fluidity in macrophages. We previously showed that differential expression of SMPDL3b alters the availability of Ceramide-1-phosphate (C1P) in human podocytes, which are terminally differentiated cells of the kidney filtration barrier. This observation lead us to investigate if SMPDL3b controls C1P availability in human podocytes by interfering with ceramide kinase (CERK) expression and function. We found that SMPDL3b interacts with CERK and can bind to C1P in vitro. Furthermore, CERK expression is reduced when SMPDL3b expression is silenced. These observations led us to propose that one of the mechanisms by which SMPDL3b influences the amount of C1P available in the podocytes is by interfering with the function of CERK thereby maintaining a balance in the levels of the C1P in podocytes.
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Affiliation(s)
- Shamroop Kumar Mallela
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
| | - Alla Mitrofanova
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Sandra Merscher
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA; Peggy and Harold Katz Family Drug Discovery Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
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Mena HA, Zubiry PR, Dizier B, Mignon V, Parborell F, Schattner M, Boisson-Vidal C, Negrotto S. Ceramide 1-Phosphate Protects Endothelial Colony–Forming Cells From Apoptosis and Increases Vasculogenesis In Vitro and In Vivo. Arterioscler Thromb Vasc Biol 2019; 39:e219-e232. [DOI: 10.1161/atvbaha.119.312766] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objective:
Ceramide 1-phosphate (C1P) is a bioactive sphingolipid highly augmented in damaged tissues. Because of its abilities to stimulate migration of murine bone marrow–derived progenitor cells, it has been suggested that C1P might be involved in tissue regeneration. In the present study, we aimed to investigate whether C1P regulates survival and angiogenic activity of human progenitor cells with great therapeutic potential in regenerative medicine such as endothelial colony–orming cells (ECFCs).
Approach and Results:
C1P protected ECFC from TNFα (tumor necrosis factor-α)-induced and monosodium urate crystal–induced death and acted as a potent chemoattractant factor through the activation of ERK1/2 (extracellular signal-regulated kinases 1 and 2) and AKT pathways. C1P treatment enhanced ECFC adhesion to collagen type I, an effect that was prevented by β1 integrin blockade, and to mature endothelial cells, which was mediated by the E-selectin/CD44 axis. ECFC proliferation and cord-like structure formation were also increased by C1P, as well as vascularization of gel plug implants loaded or not with ECFC. In a murine model of hindlimb ischemia, local administration of C1P alone promoted blood perfusion and reduced necrosis in the ischemic muscle. Additionally, the beneficial effects of ECFC infusion after ischemia were amplified by C1P pretreatment, resulting in a further and significant enhancement of leg reperfusion and muscle repair.
Conclusions:
Our findings suggest that C1P may have therapeutic relevance in ischemic disorders, improving tissue repair by itself, or priming ECFC angiogenic responses such as chemotaxis, adhesion, proliferation, and tubule formation, which result in a better outcome of ECFC-based therapy.
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Affiliation(s)
- Hebe Agustina Mena
- From the Experimental Thrombosis Laboratory, Institute of Experimental Medicine, National Academy of Medicine–CONICET, Buenos Aires, Argentina (H.A.M., P.R.Z., M.S., S.N.)
| | - Paula Romina Zubiry
- From the Experimental Thrombosis Laboratory, Institute of Experimental Medicine, National Academy of Medicine–CONICET, Buenos Aires, Argentina (H.A.M., P.R.Z., M.S., S.N.)
| | - Blandine Dizier
- Innovative Therapies in Haemostasis, INSERM (B.D., C.B.-V.), Université de Paris, France
| | - Virginie Mignon
- INSERM US025, CNRS UMRS 3612, PTICM (V.M.), Université de Paris, France
| | - Fernanda Parborell
- Experimental Medicine and Biology Institute, CONICET, Buenos Aires, Argentina (F.P.)
| | - Mirta Schattner
- From the Experimental Thrombosis Laboratory, Institute of Experimental Medicine, National Academy of Medicine–CONICET, Buenos Aires, Argentina (H.A.M., P.R.Z., M.S., S.N.)
| | | | - Soledad Negrotto
- From the Experimental Thrombosis Laboratory, Institute of Experimental Medicine, National Academy of Medicine–CONICET, Buenos Aires, Argentina (H.A.M., P.R.Z., M.S., S.N.)
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Abdelbaset-Ismail A, Cymer M, Borkowska-Rzeszotek S, Brzeźniakiewicz-Janus K, Rameshwar P, Kakar SS, Ratajczak J, Ratajczak MZ. Bioactive Phospholipids Enhance Migration and Adhesion of Human Leukemic Cells by Inhibiting Heme Oxygenase 1 (HO-1) and Inducible Nitric Oxygenase Synthase (iNOS) in a p38 MAPK-Dependent Manner. Stem Cell Rev Rep 2019; 15:139-154. [PMID: 30302660 PMCID: PMC6366663 DOI: 10.1007/s12015-018-9853-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Bioactive phospholipids, including sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), lysophosphatidylcholine (LPC), and its derivative lysophosphatidic acid (LPA), have emerged as important mediators regulating the trafficking of normal and cancer cells. While the role of S1P in regulating migration of hematopoietic cells is well established, in this work we compared its biological effects to the effects of C1P, LPC, and LPA. We employed 10 human myeloid and lymphoid cell lines as well as blasts from AML patients. We observed that human leukemic cells express functional receptors for phospholipids and respond to stimulation by phosphorylation of p42/44 MAPK and AKT. We also found that bioactive phospholipids enhanced cell migration and adhesion of leukemic cells by downregulating expression of HO-1 and iNOS in a p38 MAPK-dependent manner but did not affect cell proliferation. By contrast, downregulation of p38 MAPK by SB203580 enhanced expression of HO-1 and iNOS and decreased migration of leukemic cells in vitro and their seeding efficiency to vital organs in vivo after injection into immunodeficient mice. Based on these findings, we demonstrate that, besides S1P, human leukemic cells also respond to C1P, LPC, and LPA. Since the prometastatic effects of bioactive phospholipids in vivo were mediated, at least in part, by downregulating HO-1 and iNOS expression in a p38 MAPK-dependent manner, we propose that inhibitors of p38 MAPK or stimulators of HO-1 activity will find application in inhibiting the spread of leukemic cells in response to bioactive phospholipids.
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Affiliation(s)
- Ahmed Abdelbaset-Ismail
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
- Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Monika Cymer
- Center for Preclinical Research and Technology, Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
| | | | | | | | - Sham S Kakar
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
| | - Janina Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA
| | - Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.
- Center for Preclinical Research and Technology, Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland.
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Pascuali N, Scotti L, Di Pietro M, Oubiña G, Bas D, May M, Gómez Muñoz A, Cuasnicú PS, Cohen DJ, Tesone M, Abramovich D, Parborell F. Ceramide-1-phosphate has protective properties against cyclophosphamide-induced ovarian damage in a mice model of premature ovarian failure. Hum Reprod 2019. [PMID: 29534229 DOI: 10.1093/humrep/dey045] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
STUDY QUESTION Is ceramide-1-phosphate (C1P) an ovarian protective agent during alkylating chemotherapy? SUMMARY ANSWER Local administration of C1P drastically reduces ovarian damage induced by cyclophosphamide (Cy) via protection of follicular reserve, restoration of hormone levels, inhibition of apoptosis and improvement of stromal vasculature, while protecting fertility, oocyte quality and uterine morphology. WHAT IS KNOWN ALREADY Cancer-directed therapies cause accelerated loss of ovarian reserve and lead to premature ovarian failure (POF). Previous studies have demonstrated that C1P regulates different cellular processes including cell proliferation, cell migration, angiogenesis and apoptosis. This sphingolipid may be capable of modulating vascular development and apoptosis in ovaries affected by chemotherapy. STUDY DESIGN, SIZE, DURATION The 6-8-week-old mice were weighed and administered either a single intraperitoneal injection of Cy (75 mg/kg) or an equal volume of saline solution only for control mice. Control and Cy mice underwent sham surgery and received an intrabursal injection of saline solution, while Cy + C1P animal groups received 5 μl C1P, either 0.5 or 1 mM, under the bursa of both ovaries 1 h prior to Cy administration. PARTICIPANTS/MATERIALS, SETTING, METHODS Animals were euthanized by cervical dislocation or cardiac puncture 2 weeks after surgery for collection of blood orovary and uterus samples, which were cleaned of adhering tissue in culture medium and used for subsequent assays. Ovaries were used for Western blotting or immunohistochemical and/or histological analyses or steroid extraction, as required (n = 5-8 per group). A set of mice (n = 3/group) was destined for oocyte recovery and IVF. Finally, another set (n = 5-6/group) was separated to study fertility parameters. MAIN RESULTS AND THE ROLE OF CHANCE The number of primordial (P < 0.01), primary (P < 0.05) and preantral follicles (P < 0.05) were decreased in Cy-treated mice compared to control animals, while atretic follicles were increased (P < 0.001). In Cy + C1P mice, the ovaries recovered control numbers of these follicular structures, in both C1P doses studied. Cy affected AMH expression, while it was at least partially recovered when C1P is administered as well. Cy caused an increase in serum FSH concentration (P < 0.01), which was prevented by C1P coadministration (P < 0.01). E2 levels in Cy-treated ovaries decreased significantly compared to control ovaries (P < 0.01), whilst C1P restored E2 levels to those of control ovaries (P < 0.01). Cy increased the expression of BAX (P < 0.01) and decreased the expression of BCLX-L compared to control ovaries (P < 0.01). The ovarian BCLX-L:BAX ratio was also lower in Cy-treated mice (P < 0.05). In the Cy + C1P group, the expression levels of BAX, BCLX-L and BCLX-L:BAX ratio were no different than those in control ovaries. In addition, acid sphingomyelinase (A-SMase) expression was higher in Cy-treated ovaries, whilst remaining similar to the control in the Cy + C1P group. Cy increased the apoptotic index (TUNEL-positive follicles/total follicles) in preantral and early antral stages, compared to control ovaries (P < 0.001 and P < 0.01, respectively). C1P protected follicles from this increase. No primordial or primary follicular cells stained for either cleaved caspase-3 or TUNEL when exposed to Cy, therefore, we have found no evidence for follicular reserve depletion in response to Cy being due to apoptosis. Cy caused evident vascular injury, especially in large cortical stromal vessels, and some neovascularization. In the Cy + C1P group, the disruptions in vascular wall continuity were less evident and the number of healthy stromal blood vessels seemed to be restored. In Cy-treated ovaries α-SMA-positive cells showed a less uniform distribution around blood vessels. C1P coadministration partially prevented this Cy-induced effect, with a higher presence of α-SMA-positive cells surrounding vessels. By H&E staining, Cy-treated mice showed endometrial alterations compared to controls, affecting both epithelial and stromal compartments. However, C1P allowed that the stromal tissue to maintain its loose quality and its glandular branches. Cy-treated animals had significantly lower pregnancy rates and smaller litter sizes compared with control mice (P = 0.013 and P < 0.05, respectively), whereas cotreatment with C1P preserved normal fertility. Furthermore, a higher (P < 0.05) proportion of abnormal oocytes was recovered from Cy-treated mice compared to the control, which was prevented by C1P administration. LARGE SCALE DATA N/A. LIMITATIONS REASONS FOR CAUTION The results of this study were generated from an in-vivo animal experimental model, already used by several authors. Further studies on C1P functions in female reproduction in pathological conditions such as chemotherapy-induced ovarian failure and on the safety of use of this sphingolipid are required. WIDER IMPLICATIONS OF THE FINDINGS The present findings showed that C1P administration prior to Cy might be a promising fertility preservation strategy in female patients who undergo chemotherapy. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants from ANPCyT (PICT 2015-1117), CONICET (PIP 380), Cancer National Institute (INC) and Roemmers Foundation, Argentina. The authors declare no conflicts of interest.
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Affiliation(s)
- Natalia Pascuali
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Leopoldina Scotti
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Mariana Di Pietro
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Gonzalo Oubiña
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Diana Bas
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - María May
- Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Antonio Gómez Muñoz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Bilbao, Spain
| | - Patricia S Cuasnicú
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Débora J Cohen
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Marta Tesone
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Dalhia Abramovich
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - Fernanda Parborell
- IInstituto de Biología y Medicina Experimental (IByME-CONICET), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
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Wang W, Toran PT, Sabol R, Brown TJ, Barth BM. Epigenetics and Sphingolipid Metabolism in Health and Disease. ACTA ACUST UNITED AC 2019; 1. [PMID: 30637412 DOI: 10.31021/ijbs.20181105] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Sphingolipids represent one of the major classes of bioactive lipids. Studies of sphingolipids have intensified in the past several years, revealing their roles in nearly all cell biological processes. In addition, epigenetic regulation has gained substantial interest due to its role in controlling gene expression and activity without changing the genetic code. In this review, we first introduce a brief background on sphingolipid biology, highlighting its role in pathophysiology. We then illustrate the concept of epigenetic regulation, focusing on how it affects the metabolism of sphingolipids. We further discuss the roles of bioactive sphingolipids as epigenetic regulators themselves. Overall, a better understanding of the relationship between epigenetics and sphingolipid metabolism may help to improve the development of sphingolipid-targeted therapeutics.
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Affiliation(s)
- Weiyuan Wang
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH 03824 USA
| | - Paul T Toran
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH 03824 USA
| | - Rachel Sabol
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH 03824 USA
| | - Timothy J Brown
- Department of Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
| | - Brian M Barth
- Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH 03824 USA
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26
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Bujko K, Kucia M, Ratajczak J, Ratajczak MZ. Hematopoietic Stem and Progenitor Cells (HSPCs). ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:49-77. [PMID: 31898781 DOI: 10.1007/978-3-030-31206-0_3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hematopoietic stem/progenitor cells (HSPCs) isolated from bone marrow have been successfully employed for 50 years in hematological transplantations. Currently, these cells are more frequently isolated from mobilized peripheral blood or umbilical cord blood. In this chapter, we overview several topics related to these cells including their phenotype, methods for isolation, and in vitro and in vivo assays to evaluate their proliferative potential. The successful clinical application of HSPCs is widely understood to have helped establish the rationale for the development of stem cell therapies and regenerative medicine.
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Affiliation(s)
- Kamila Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Magda Kucia
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Janina Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Mariusz Z Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Warsaw Medical University, Warsaw, Poland.
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27
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Skonieczna-Żydecka K, Marlicz W, Misera A, Koulaouzidis A, Łoniewski I. Microbiome-The Missing Link in the Gut-Brain Axis: Focus on Its Role in Gastrointestinal and Mental Health. J Clin Med 2018; 7:E521. [PMID: 30544486 PMCID: PMC6306769 DOI: 10.3390/jcm7120521] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/02/2018] [Accepted: 12/05/2018] [Indexed: 12/12/2022] Open
Abstract
The central nervous system (CNS) and the human gastrointestinal (GI) tract communicate through the gut-brain axis (GBA). Such communication is bi-directional and involves neuronal, endocrine, and immunological mechanisms. There is mounting data that gut microbiota is the source of a number of neuroactive and immunocompetent substances, which shape the structure and function of brain regions involved in the control of emotions, cognition, and physical activity. Most GI diseases are associated with altered transmission within the GBA that are influenced by both genetic and environmental factors. Current treatment protocols for GI and non-GI disorders may positively or adversely affect the composition of intestinal microbiota with a diverse impact on therapeutic outcome(s). Alterations of gut microbiota have been associated with mood and depressive disorders. Moreover, mental health is frequently affected in GI and non-GI diseases. Deregulation of the GBA may constitute a grip point for the development of diagnostic tools and personalized microbiota-based therapy. For example, next generation sequencing (NGS) offers detailed analysis of microbiome footprints in patients with mental and GI disorders. Elucidating the role of stem cell⁻host microbiome cross talks in tissues in GBA disorders might lead to the development of next generation diagnostics and therapeutics. Psychobiotics are a new class of beneficial bacteria with documented efficacy for the treatment of GBA disorders. Novel therapies interfering with small molecules involved in adult stem cell trafficking are on the horizon.
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Affiliation(s)
- Karolina Skonieczna-Żydecka
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland.
| | - Wojciech Marlicz
- Department of Gastroenterology, Pomeranian Medical University, 71-252 Szczecin, Poland.
| | - Agata Misera
- Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, 13353 Berlin, Germany.
| | | | - Igor Łoniewski
- Department of Biochemistry and Human Nutrition, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland.
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Yu J, Kim HM, Kim KP, Son Y, Kim MS, Park KS. Ceramide kinase regulates the migration of bone marrow-derived mesenchymal stem cells. Biochem Biophys Res Commun 2018; 508:361-367. [PMID: 30502084 DOI: 10.1016/j.bbrc.2018.11.154] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 11/22/2018] [Indexed: 11/18/2022]
Abstract
Endogenous bone marrow-derived mesenchymal stem cells (BM-MSCs) are mobilized into peripheral blood and injured tissues by various growth factors and cytokines that are expressed in the injured tissues, such as substance P (SP), stromal cell derived factor-1 (SDF-1), and transforming growth factor-beta (TGF-β). Extracellular bioactive lipid metabolites such as ceramide-1-phosphate and sphingosine-1-phosphate also modulate BM-MSC migration as SP, SDF-1, and TGF-β. However, the roles of intrinsic lipid kinases of BM-MSCs in the stem cell migration are unclear. Here, we demonstrated that ceramide kinase mediates the chemotactic migration of BM-MSCs in response to SP, SDF-1, or TGF-β. Furthermore, a specific inhibitor of ceramide kinase inhibited TGF-β-induced migration of BM-MSCs and N-cadherin that is necessary for BM-MSCs migration in response to TGF-β. Therefore, these results suggest that the intracellular ceramide kinase is required for the BM-MSCs migration and the roles of the intrinsic ceramide kinase in the migration are associated with N-cadherin regulation.
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Affiliation(s)
- Jinyeong Yu
- Graduate School of Biotechnology, Kyung Hee University, Yongin, 17104, South Korea
| | - Hye Min Kim
- Department of Applied Chemistry, Kyung Hee University, Yongin, 17104, South Korea
| | - Kwang Pyo Kim
- Department of Applied Chemistry, Kyung Hee University, Yongin, 17104, South Korea
| | - Youngsook Son
- Graduate School of Biotechnology, Kyung Hee University, Yongin, 17104, South Korea
| | - Min-Sik Kim
- Department of Applied Chemistry, Kyung Hee University, Yongin, 17104, South Korea; Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, 02447, South Korea; Department of New Biology, DGIST, Daegu, 42988, South Korea.
| | - Ki-Sook Park
- Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, 02447, South Korea; East-West Medical Research Institute, Kyung Hee University, Seoul, 02447, South Korea; Kyung Hee University Medical Center, Seoul, 02447, South Korea.
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29
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Regulation of adipogenesis by ceramide 1-phosphate. Exp Cell Res 2018; 372:150-157. [DOI: 10.1016/j.yexcr.2018.09.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 09/24/2018] [Accepted: 09/26/2018] [Indexed: 11/27/2022]
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Ng ML, Yarla NS, Menschikowski M, Sukocheva OA. Regulatory role of sphingosine kinase and sphingosine-1-phosphate receptor signaling in progenitor/stem cells. World J Stem Cells 2018; 10:119-133. [PMID: 30310531 PMCID: PMC6177561 DOI: 10.4252/wjsc.v10.i9.119] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 07/27/2018] [Accepted: 08/05/2018] [Indexed: 02/06/2023] Open
Abstract
Balanced sphingolipid signaling is important for the maintenance of homeostasis. Sphingolipids were demonstrated to function as structural components, second messengers, and regulators of cell growth and survival in normal and disease-affected tissues. Particularly, sphingosine kinase 1 (SphK1) and its product sphingosine-1-phosphate (S1P) operate as mediators and facilitators of proliferation-linked signaling. Unlimited proliferation (self-renewal) within the regulated environment is a hallmark of progenitor/stem cells that was recently associated with the S1P signaling network in vasculature, nervous, muscular, and immune systems. S1P was shown to regulate progenitor-related characteristics in normal and cancer stem cells (CSCs) via G-protein coupled receptors S1Pn (n = 1 to 5). The SphK/S1P axis is crucially involved in the regulation of embryonic development of vasculature and the nervous system, hematopoietic stem cell migration, regeneration of skeletal muscle, and development of multiple sclerosis. The ratio of the S1P receptor expression, localization, and specific S1P receptor-activated downstream effectors influenced the rate of self-renewal and should be further explored as regeneration-related targets. Considering malignant transformation, it is essential to control the level of self-renewal capacity. Proliferation of the progenitor cell should be synchronized with differentiation to provide healthy lifelong function of blood, immune systems, and replacement of damaged or dead cells. The differentiation-related role of SphK/S1P remains poorly assessed. A few pioneering investigations explored pharmacological tools that target sphingolipid signaling and can potentially confine and direct self-renewal towards normal differentiation. Further investigation is required to test the role of the SphK/S1P axis in regulation of self-renewal and differentiation.
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Affiliation(s)
- Mei Li Ng
- Centenary Institute of Cancer Medicine and Cell Biology, Sydney NSW 2050, Australia
| | - Nagendra S Yarla
- Department of Biochemistry and Bioinformatics, Institute of Science, GITAM University, Rushikonda, Visakhapatnam 530 045, Andhra Pradesh, India
| | - Mario Menschikowski
- Institute of Clinical Chemistry and Laboratory Medicine, Carl Gustav Carus University Hospital, Technical University of Dresden, Dresden D-01307, Germany
| | - Olga A Sukocheva
- College of Nursing and Health Sciences, Flinders University of South Australia, Bedford Park SA 5042, Australia.
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Kuc N, Doermann A, Shirey C, Lee DD, Lowe CW, Awasthi N, Schwarz RE, Stahelin RV, Schwarz MA. Pancreatic ductal adenocarcinoma cell secreted extracellular vesicles containing ceramide-1-phosphate promote pancreatic cancer stem cell motility. Biochem Pharmacol 2018; 156:458-466. [PMID: 30222969 DOI: 10.1016/j.bcp.2018.09.017] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 09/13/2018] [Indexed: 02/06/2023]
Abstract
The high mortality rate associated with pancreatic ductal adenocarcinoma (PDAC) is in part due to lack of effective therapy for this highly chemoresistant tumor. Cancer stem cells, a subset of cancer cells responsible for tumor initiation and metastasis, are not targeted by conventional cytotoxic agents, which renders the identification of factors that facilitate cancer stem cell activation useful in defining targetable mechanisms. We determined that bioactive sphingolipid induced migration of pancreatic cancer stem cells (PCSC) and signaling was specific to ceramide-1-phosphate (C1P). Furthermore, PDAC cells were identified as a rich source of C1P. Importantly, PDAC cells express the C1P converting enzyme ceramide kinase (CerK), secrete C1P-containing extracellular vesicles that mediate PCSC migration, and when co-injected with PCSC reduce animal survival in a PDAC peritoneal dissemination model. Our findings suggest that PDAC secrete C1P-containing extracellular vesicles as a means of recruiting PCSC to sustain tumor growth therefore making C1P release a mechanism that could facilitate tumor progression.
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Affiliation(s)
- Norbert Kuc
- Department of Biological Sciences, University of Notre Dame, United States
| | - Allison Doermann
- Department of Biological Sciences, University of Notre Dame, United States
| | - Carolyn Shirey
- Department of Chemistry and Biochemistry, University of Notre Dame, United States
| | - Daniel D Lee
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, United States; Department of Pediatrics, Indiana University School of Medicine, United States
| | - Chinn-Woan Lowe
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, United States
| | - Niranjan Awasthi
- Department of Surgery, Indiana University School of Medicine, United States
| | - Roderich E Schwarz
- Department of Surgery, Indiana University School of Medicine, United States; Department of Goshen Center for Cancer Care, Goshen, IN, United States
| | - Robert V Stahelin
- Department of Chemistry and Biochemistry, University of Notre Dame, United States; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, United States
| | - Margaret A Schwarz
- Department of Chemistry and Biochemistry, University of Notre Dame, United States; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, United States; Department of Pediatrics, Indiana University School of Medicine, United States.
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Federico L, Yang L, Brandon J, Panchatcharam M, Ren H, Mueller P, Sunkara M, Escalante-Alcalde D, Morris AJ, Smyth SS. Lipid phosphate phosphatase 3 regulates adipocyte sphingolipid synthesis, but not developmental adipogenesis or diet-induced obesity in mice. PLoS One 2018; 13:e0198063. [PMID: 29889835 PMCID: PMC5995365 DOI: 10.1371/journal.pone.0198063] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 03/22/2018] [Indexed: 01/13/2023] Open
Abstract
Dephosphorylation of phosphatidic acid (PA) is the penultimate step in triglyceride synthesis. Adipocytes express soluble intracellular PA-specific phosphatases (Lipins) and broader specificity membrane-associated lipid phosphate phosphatases (LPPs) that can also dephosphorylate PA. Inactivation of lipin1 causes lipodystrophy in mice due to defective developmental adipogenesis. Triglyceride synthesis is diminished but not ablated by inactivation of lipin1 in differentiated adipocytes implicating other PA phosphatases in this process. To investigate the possible role of LPPs in adipocyte lipid metabolism and signaling we made mice with adipocyte-targeted inactivation of LPP3 encoded by the Plpp3(Ppap2b) gene. Adipocyte LPP3 deficiency resulted in blunted ceramide and sphingomyelin accumulation during diet-induced adipose tissue expansion, accumulation of the LPP3 substrate sphingosine 1- phosphate, and reduced expression of serine palmitoyl transferase. However, adiposity was unaffected by LPP3 deficiency on standard, high fat diet or Western diets, although Western diet-fed mice with adipocyte LPP3 deficiency exhibited improved glucose tolerance. Our results demonstrate functional compartmentalization of lipid phosphatase activity in adipocytes and identify an unexpected role for LPP3 in the regulation of diet-dependent sphingolipid synthesis that may impact on insulin signaling.
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Affiliation(s)
- Lorenzo Federico
- Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, United States of America
| | - Liping Yang
- Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, United States of America
| | - Jason Brandon
- Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, United States of America
| | - Manikandan Panchatcharam
- Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, United States of America
| | - Hongmei Ren
- Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, United States of America
| | - Paul Mueller
- Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, United States of America
| | - Manjula Sunkara
- Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, United States of America
| | - Diana Escalante-Alcalde
- División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad de México, CDMX, México
| | - Andrew J. Morris
- Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, United States of America
- Department of Veterans Affairs Medical Center, Lexington, Kentucky, United States of America
| | - Susan S. Smyth
- Division of Cardiovascular Medicine, The Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, United States of America
- Department of Veterans Affairs Medical Center, Lexington, Kentucky, United States of America
- * E-mail:
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Abstract
Ceramide 1-phosphate (C1P) is a pleiotropic bioactive sphingolipid metabolite capable of regulating key physiologic cell functions and promoting pathologic processes. Concerning pathology, C1P or ceramide kinase (CerK), the enzyme responsible for its biosynthesis in mammalian cells, has been implicated in cancer cell growth, survival, and dissemination and is involved in inflammatory responses associated with different types of cancer cells. The mechanisms or signaling pathways mediating these C1P actions have only been partially described. This chapter reviews recent progress in identifying signal transduction pathways involved in the promotion of cancer cell growth, survival, and dissemination by CerK and C1P.
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Affiliation(s)
- Antonio Gomez-Muñoz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Bilbao, Spain
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Sukocheva OA. Expansion of Sphingosine Kinase and Sphingosine-1-Phosphate Receptor Function in Normal and Cancer Cells: From Membrane Restructuring to Mediation of Estrogen Signaling and Stem Cell Programming. Int J Mol Sci 2018; 19:420. [PMID: 29385066 PMCID: PMC5855642 DOI: 10.3390/ijms19020420] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 01/21/2018] [Accepted: 01/24/2018] [Indexed: 02/05/2023] Open
Abstract
Sphingolipids, sphingolipid metabolizing enzymes, and their receptors network are being recognized as part of the signaling mechanisms, which govern breast cancer cell growth, migration, and survival during chemotherapy treatment. Approximately 70% of breast cancers are estrogen receptor (ER) positive and, thus, rely on estrogen signaling. Estrogen activates an intracellular network composed of many cytoplasmic and nuclear mediators. Some estrogen effects can be mediated by sphingolipids. Estrogen activates sphingosine kinase 1 (SphK1) and amplifies the intracellular concentration of sphingosine-1-phosphate (S1P) in breast cancer cells during stimulation of proliferation and survival. Specifically, Estrogen activates S1P receptors (S1PR) and induces growth factor receptor transactivation. SphK, S1P, and S1PR expression are causally associated with endocrine resistance and progression to advanced tumor stages in ER-positive breast cancers in vivo. Recently, the network of SphK/S1PR was shown to promote the development of ER-negative cancers and breast cancer stem cells, as well as stimulating angiogenesis. Novel findings confirm and broaden our knowledge about the cross-talk between sphingolipids and estrogen network in normal and malignant cells. Current S1PRs therapeutic inhibition was indicated as a promising chemotherapy approach in non-responsive and advanced malignancies. Considering that sphingolipid signaling has a prominent role in terminally differentiated cells, the impact should be considered when designing specific SphK/S1PR inhibitors. This study analyzes the dynamic of the transformation of sphingolipid axis during a transition from normal to pathological condition on the level of the whole organism. The sphingolipid-based mediation and facilitation of global effects of estrogen were critically accented as a bridging mechanism that should be explored in cancer prevention.
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Affiliation(s)
- Olga A Sukocheva
- College of Nursing and Health Sciences, Flinders University of South Australia, Bedford Park, SA 5042, Australia.
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Bernacchioni C, Cencetti F, Ouro A, Bruno M, Gomez-Muñoz A, Donati C, Bruni P. Lysophosphatidic Acid Signaling Axis Mediates Ceramide 1-Phosphate-Induced Proliferation of C2C12 Myoblasts. Int J Mol Sci 2018; 19:ijms19010139. [PMID: 29300303 PMCID: PMC5796088 DOI: 10.3390/ijms19010139] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Revised: 12/23/2017] [Accepted: 12/28/2017] [Indexed: 02/07/2023] Open
Abstract
Sphingolipids are not only crucial for membrane architecture but act as critical regulators of cell functions. The bioactive sphingolipid ceramide 1-phosphate (C1P), generated by the action of ceramide kinase, has been reported to stimulate cell proliferation, cell migration and to regulate inflammatory responses via activation of different signaling pathways. We have previously shown that skeletal muscle is a tissue target for C1P since the phosphosphingolipid plays a positive role in myoblast proliferation implying a role in muscle regeneration. Skeletal muscle displays strong capacity of regeneration thanks to the presence of quiescent adult stem cells called satellite cells that upon trauma enter into the cell cycle and start proliferating. However, at present, the exact molecular mechanism by which C1P triggers its mitogenic effect in myoblasts is lacking. Here, we report for the first time that C1P stimulates C2C12 myoblast proliferation via lysophosphatidic acid (LPA) signaling axis. Indeed, C1P subsequently to phospholipase A2 activation leads to LPA1 and LPA3 engagement, which in turn drive Akt (protein kinase B) and ERK1/2 (extracellular signal-regulated kinases 1/2) activation, thus stimulating DNA synthesis. The present findings shed new light on the key role of bioactive sphingolipids in skeletal muscle and provide further support to the notion that these pleiotropic molecules might be useful therapeutic targets for skeletal muscle regeneration.
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Affiliation(s)
- Caterina Bernacchioni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134 Firenze, Italy.
- Istituto Interuniversitario di Miologia (IIM), Italy.
| | - Francesca Cencetti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134 Firenze, Italy.
- Istituto Interuniversitario di Miologia (IIM), Italy.
| | - Alberto Ouro
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
- Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
| | - Marina Bruno
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134 Firenze, Italy.
| | - Antonio Gomez-Muñoz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
| | - Chiara Donati
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134 Firenze, Italy.
- Istituto Interuniversitario di Miologia (IIM), Italy.
| | - Paola Bruni
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Viale GB Morgagni 50, 50134 Firenze, Italy.
- Istituto Interuniversitario di Miologia (IIM), Italy.
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Ratajczak MZ, Ciechanowicz AK, Kucharska-Mazur J, Samochowiec J. Stem cells and their potential clinical applications in psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2018; 80:3-9. [PMID: 28435007 PMCID: PMC5623088 DOI: 10.1016/j.pnpbp.2017.04.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/17/2017] [Accepted: 04/19/2017] [Indexed: 12/23/2022]
Abstract
The robustness of stem cells is one of the major factors that directly impacts life quality and life span. Evidence has accumulated that changes in the stem cell compartment affect human mental health and serve as an indicator of psychiatric problems. It is well known that stem cells continuously replace differentiated cells and tissues that are used up during life, although this replacement occurs at a different pace in the various organs. However, the participation of local neural stem cells in regeneration of the central nervous system is controversial. It is known that low numbers of stem cells circulate continuously in peripheral blood (PB) and lymph and undergo a circadian rhythm in their PB level, with the peak occurring early in the morning and the nadir at night, and recent evidence suggests that the number and pattern of circulating stem cells in PB changes in psychotic disorders. On the other hand, progress in the creation of induced pluripotent stem cells (iPSCs) from patient somatic cells provides valuable tools with which to study changes in gene expression in psychotic patients. We will discuss the various potential sources of stem cells that are currently employed in regenerative medicine and the mechanisms that explain some of their beneficial effects as well as the emerging problems with stem cell therapies. However, the main question remains: Will it be possible in the future to modulate the stem cell compartment to reverse psychiatric problems?
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Affiliation(s)
- Mariusz Z Ratajczak
- Stem Cell Institute, 500 South Floyd Street, James Graham Brown Cancer Center, University of Louisville, Louisville 40202, KY, USA; Department of Regenerative Medicine Warsaw Medical University, Warsaw, Poland.
| | | | | | - Jerzy Samochowiec
- Department of Psychiatry, Pomeranian Medical University, Szczecin, Poland
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Jia Y, Gan Y, He C, Chen Z, Zhou C. The mechanism of skin lipids influencing skin status. J Dermatol Sci 2017; 89:112-119. [PMID: 29174114 DOI: 10.1016/j.jdermsci.2017.11.006] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 11/14/2017] [Indexed: 02/06/2023]
Abstract
Skin lipids, compose of sebocyte-, keratinocyte-, and microbe- derived lipids, dramatically influence skin status by different mechanisms. (I) Physical chemistry function: They are "mortar" to establish the physico-chemical barrier function of skin; (II) Biochemistry function: They function as signals in the complex signaling network originating at the epidermal level; (III) Microecology function: Sebocyte- and keratinocyte-derived lipids vary the composition of microbial skin flora, and microorganisms metabolize them to produce lipids as signal starting signaling transduction. Importantly, further research needs lipidiomics, more powerful analytical ability and high-throughput manner, to identify skin lipid components into individual species. The validation of lipid structure and function to research the process that lipid species involved in. Additional, the integration of lipidomics data with other omics strategies can develop the power to study the mechanism of skin lipids influencing skin status.
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Affiliation(s)
- Yan Jia
- Beijing Key Laboratory of Plant Resources Research and Development, School of Science, Beijing Technology and Business University, Beijing 100048, China.
| | - Yao Gan
- Beijing Key Laboratory of Plant Resources Research and Development, School of Science, Beijing Technology and Business University, Beijing 100048, China
| | - Congfen He
- Beijing Key Laboratory of Plant Resources Research and Development, School of Science, Beijing Technology and Business University, Beijing 100048, China
| | - Zhou Chen
- Department of Dermatology, Peking University People's Hospital, Beijing, China
| | - Cheng Zhou
- Department of Dermatology, Peking University People's Hospital, Beijing, China
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The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer. Mediators Inflamm 2017; 2017:4806541. [PMID: 29269995 PMCID: PMC5705877 DOI: 10.1155/2017/4806541] [Citation(s) in RCA: 140] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 08/01/2017] [Accepted: 08/30/2017] [Indexed: 01/02/2023] Open
Abstract
Inflammation is part of our body's response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK) to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs). Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field.
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Ouro A, Arana L, Riazy M, Zhang P, Gomez-Larrauri A, Steinbrecher U, Duronio V, Gomez-Muñoz A. Vascular endothelial growth factor mediates ceramide 1-phosphate-stimulated macrophage proliferation. Exp Cell Res 2017; 361:277-283. [PMID: 29080796 DOI: 10.1016/j.yexcr.2017.10.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 10/07/2017] [Accepted: 10/24/2017] [Indexed: 12/12/2022]
Abstract
The bioactive sphingolipid ceramide 1-phosphate (C1P) regulates cell division in a variety of cell types including macrophages. However, the mechanisms involved in this action are not completely understood. In the present work we show that C1P stimulates the release of vascular endothelial growth factor (VEGF) in RAW264.7 macrophages, and that this growth factor is essential for stimulation of cell proliferation by C1P. The stimulation of VEGF release was dependent upon activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB-1 also known as Akt-1), and mitogen-activated protein kinase-kinase (MEK)/extracellularly regulated kinase-2 (ERK-2) pathways, as inhibition of these kinases with selective pharmacological inhibitors or with specific gene silencing siRNA, abrogated VEGF release. A key observation was that sequestration of VEGF with a neutralizing antibody, or treatment with VEGF siRNA abolished C1P-stimulated macrophage growth. Also, inhibition of the pathways involved in C1P-stimulated VEGF release inhibited the stimulation of macrophage growth by C1P. Moreover, blockade of VEGF receptor-2 (VEGFR-2), which is the primary receptor for VEGF, with the pharmacological inhibitor DMH4, or with specific VEGFR-2 siRNA, substantially inhibited C1P-stimulated cell growth. It can be concluded that stimulation of VEGF release is a key factor in the promotion of macrophage proliferation by C1P.
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Affiliation(s)
- Alberto Ouro
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain
| | - Lide Arana
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain
| | - Maziar Riazy
- Department of Medicine. University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Peng Zhang
- Department of Medicine. University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Ana Gomez-Larrauri
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain
| | - Urs Steinbrecher
- Department of Medicine. University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Vincent Duronio
- Department of Medicine. University of British Columbia and Vancouver Coastal Health Research Institute, Vancouver, British Columbia, Canada
| | - Antonio Gomez-Muñoz
- Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, Spain.
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40
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Jefferson GE, Schnell DM, Thomas DT, Bollinger LM. Calcitriol concomitantly enhances insulin sensitivity and alters myocellular lipid partitioning in high fat-treated skeletal muscle cells. J Physiol Biochem 2017; 73:613-621. [PMID: 28980208 DOI: 10.1007/s13105-017-0595-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 09/25/2017] [Indexed: 02/08/2023]
Abstract
Vitamin D reduces myocellular insulin resistance, but the effects of vitamin D on intramyocellular lipid (IMCL) partitioning are unknown. The purpose of this study was to understand how calcitriol, the active vitamin D metabolite, affects insulin sensitivity and lipid partitioning in skeletal muscle cells. C2C12 myotubes were treated with calcitriol (100 nM) or vehicle control for 96 h. Insulin-stimulated Akt phosphorylation (Thr 308) was determined by western blot. Intramyocellular triacylglycerol (IMTG), diacylglycerol (DAG), and ceramide content were measured by LC/MS. IMTG partitioning and lipid droplet accumulation were assessed by oil red O. Expression of genes involved in lipid droplet packaging and lipolysis were measured by RT-PCR. Compared to vehicle-treated myotubes, calcitriol augmented insulin-stimulated pAkt. Calcitriol increased total ceramides and DAG in a subspecies-specific manner. Specifically, calcitriol preferentially increased ceramide 24:1 (1.78 fold) and di-18:0 DAG (46.89 fold). Calcitriol increased total IMTG area as assessed by oil red O, but decreased the proportion of lipid within myotubes. Calcitriol increased mRNA content of genes involved in lipid droplet packaging (perilipin 2; PLIN 2, 2.07 fold) and lipolysis (comparative gene identification-58; CGI-58 and adipose triglyceride lipase; ATGL, ~ 1.80 fold). Calcitriol alters myocellular lipid partitioning and lipid droplet packaging which may favor lipid turnover and partially explain improvements in insulin sensitivity.
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Affiliation(s)
- Grace E Jefferson
- Department of Kinesiology and Health Promotion, University of Kentucky, 201 Seaton Bldg, Lexington, KY, 40506, USA
| | - David M Schnell
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - D Travis Thomas
- College of Health Sciences, University of Kentucky, Lexington, KY, USA.,Center for Muscle Biology, University of Kentucky, Lexington, KY, USA
| | - Lance M Bollinger
- Department of Kinesiology and Health Promotion, University of Kentucky, 201 Seaton Bldg, Lexington, KY, 40506, USA. .,Center for Muscle Biology, University of Kentucky, Lexington, KY, USA.
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Adamiak M, Chelvarajan L, Lynch KR, Santos WL, Abdel-Latif A, Ratajczak MZ. Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells. Oncotarget 2017; 8:65588-65600. [PMID: 29029455 PMCID: PMC5630355 DOI: 10.18632/oncotarget.19514] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Accepted: 07/14/2017] [Indexed: 11/25/2022] Open
Abstract
Sphingosine-1-phosphate (S1P) is a bioactive lipid involved in cell signaling and, if released from cells, also plays a crucial role in regulating the trafficking of lympho-hematopoietic cells, including primitive hematopoietic stem/progenitor cells (HSPCs). It has been demonstrated that S1P chemoattracts HSPCs, and its level in peripheral blood creates a gradient directing egress of these cells during mobilization. In this paper we analyzed hematopoiesis in mice deficient in sphingosine kinase 2 (Sphk2-KO mice) and studied the effect of this mutation on plasma S1P levels. We found that Sphk2-KO mice have normal hematopoiesis, and, in contrast to Sphk1-KO mice, the circulating S1P level is highly elevated in these animals and correlates with the fact that HSPCs in Sphk2-KO animals, also in contrast to Sphk1-KO animals, show enhanced mobilization. These results were recapitulated in wild type (WT) animals employing an Sphk2 inhibitor. We also administered an inhibitor of the S1P-degrading enzyme S1P lyase, known as tetrahydroxybutylimidazole (THI), to WT mice and observed that this resulted in an increase in S1P level in PB and enhanced mobilization of HSPCs. In sum, our results support a crucial role for S1P gradients in blood plasma in the mobilization process and indicate that small-molecule inhibitors of Sphk2 and Sgpl1 could be employed as mobilization-facilitating compounds. At the same time, further studies are needed to explain the unexpected effect of Sphk2 inhibition on increasing S1P levels in plasma.
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Affiliation(s)
- Mateusz Adamiak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
| | - Lakshman Chelvarajan
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
| | - Kevin R. Lynch
- Department of Pharmacology University of Virginia, Charlottesville, VA, USA
| | - Webster L. Santos
- Department of Chemistry, Center for Drug Discovery, Virginia Tech, Blacksburg, VA, USA
| | - Ahmed Abdel-Latif
- Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA
| | - Mariusz Z. Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Department of Regenerative Medicine, Warsaw Medical University, Warsaw, Poland
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Schneider G, Sellers ZP, Bujko K, Kakar SS, Kucia M, Ratajczak MZ. Novel pleiotropic effects of bioactive phospholipids in human lung cancer metastasis. Oncotarget 2017; 8:58247-58263. [PMID: 28938552 PMCID: PMC5601648 DOI: 10.18632/oncotarget.17461] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 04/15/2017] [Indexed: 12/16/2022] Open
Abstract
We previously proposed that one of the unwanted side effects of chemotherapy and radiotherapy is the increase in several peptide- and non-peptide based chemoattractants in damaged tissues, leading to induction of a prometastatic microenvironment for remaining cancer cells. Herein, we turned out our attention to a potential role of bioactive phospholipids (BphsLs), such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), lysophosphatidylcholine (LPC), and lysophosphatidic acid (LPA) in lung cancer (LC) metastasis. We report that LC cells express several functional BphL receptors (for S1P, LPC, and LPA) as well as several enzymes involved in their metabolism and that BphsLs are potent chemokinetic and adhesion factors for these cells. We also demonstrate for the first time the novel role of C1P as a prometastatic factor in LC cells. In addition to their chemokinetic activities, BphsLs also sensitize or prime the chemotactic responsiveness of LC cells to known prometastatic factors such as hepatocyte growth factor/scatter factor (HGF/SF). Thus, for the first time we demonstrate a prometastatic effect that is based on the priming of a cell's responsiveness to chemotactic factors by chemokinetic factors. To our surprise, none of the bioactive lipids induced proliferation of LC cells or ameliorated toxic effects of vincristine treatment. Interestingly, BphsLs increase adhesion of LC cells to bone marrow-derived stromal cells and stimulate these cells to release ExNs, which additionally increase LC cell motility. In conclusion, our results show that BphsLs are important modulators of prometastatic environment. Therefore, their inhibitors could be considered as potential anti-metastatic drug candidates to be included as a part of post radio- and/or chemo- therapy treatment.
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Affiliation(s)
- Gabriela Schneider
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
| | - Zachariah Payne Sellers
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
| | - Kamila Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
| | - Sham S. Kakar
- Department of Physiology and James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
| | - Magda Kucia
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
- Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Mariusz Z. Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA
- Department of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland
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Lim J, Lee S, Ju H, Kim Y, Heo J, Lee HY, Choi KC, Son J, Oh YM, Kim IG, Shin DM. Valproic acid enforces the priming effect of sphingosine-1 phosphate on human mesenchymal stem cells. Int J Mol Med 2017; 40:739-747. [PMID: 28677769 PMCID: PMC5547989 DOI: 10.3892/ijmm.2017.3053] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 06/01/2017] [Indexed: 12/26/2022] Open
Abstract
Engraftment and homing of mesenchymal stem cells (MSCs) are modulated by priming factors including the bioactive lipid sphingosine-1-phosphate (S1P), by stimulating CXCR4 receptor signaling cascades. However, limited in vivo efficacy and the remaining priming molecules prior to administration of MSCs can provoke concerns regarding the efficiency and safety of MSC priming. Here, we showed that valproic acid (VPA), a histone deacetylase inhibitor, enforced the priming effect of S1P at a low dosage for human umbilical cord-derived MSCs (UC-MSCs). A DNA-methylation inhibitor, 5-azacytidine (5-Aza), and VPA increased the expression of CXCR4 in UC-MSCs. In particular, UC-MSCs primed with a suboptimal dose (50 nM) of S1P in combination with 0.5 mM VPA (VPA+S1P priming), but not 1 µM 5-Aza, significantly improved the migration activity in response to stromal cell-derived factor 1 (SDF-1) concomitant with the activation of both MAPKp42/44 and AKT signaling cascades. Both epigenetic regulatory compounds had little influence on cell surface marker phenotypes and the multi-potency of UC-MSCs. In contrast, VPA+S1P priming of UC-MSCs potentiated the proliferation, colony forming unit-fibroblast, and anti-inflammatory activities, which were severely inhibited in the case of 5-Aza treatment. Accordingly, the VPA+S1P-primed UC-MSCs exhibited upregulation of a subset of genes related to stem cell migration and anti-inflammation response. Thus, the present study demonstrated that VPA enables MSC priming with S1P at a low dosage by enhancing their migration and other therapeutic beneficial activities. This priming strategy for MSCs may provide a more efficient and safe application of MSCs for treating a variety of intractable disorders.
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Affiliation(s)
- Jisun Lim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Seungun Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Hyein Ju
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Yonghwan Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Jinbeom Heo
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Hye-Yeon Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Kyung-Chul Choi
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Jaekyoung Son
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Yeon-Mok Oh
- Department of Pulmonary and Critical Care Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - In-Gyu Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Dong-Myung Shin
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
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Mesev EV, Miller DS, Cannon RE. Ceramide 1-Phosphate Increases P-Glycoprotein Transport Activity at the Blood-Brain Barrier via Prostaglandin E2 Signaling. Mol Pharmacol 2017; 91:373-382. [PMID: 28119480 PMCID: PMC5363708 DOI: 10.1124/mol.116.107169] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 01/19/2017] [Indexed: 11/22/2022] Open
Abstract
P-glycoprotein, an ATP-driven efflux pump, regulates permeability of the blood-brain barrier (BBB). Sphingolipids, endogenous to brain tissue, influence inflammatory responses and cell survival in vitro. Our laboratory has previously shown that sphingolipid signaling by sphingosine 1-phosphate decreases basal P-glycoprotein transport activity. Here, we investigated the potential for another sphingolipid, ceramide 1-phosphate (C1P), to modulate efflux pumps at the BBB. Using confocal microscopy and measuring luminal accumulation of fluorescent substrates, we assessed the transport activity of several efflux pumps in isolated rat brain capillaries. C1P treatment induced P-glycoprotein transport activity in brain capillaries rapidly and reversibly. In contrast, C1P did not affect transport activity of two other major efflux transporters, multidrug resistance protein 2 and breast cancer resistance protein. C1P induced P-glycoprotein transport activity without changing transporter protein expression. Inhibition of the key signaling components in the cyclooxygenase-2 (COX-2)/prostaglandin E2 signaling cascade (phospholipase A2, COX-2, multidrug resistance protein 4, and G-protein-coupled prostaglandin E2 receptors 1 and 2), abolished P-glycoprotein induction by C1P. We show that COX-2 and prostaglandin E2 are required for C1P-mediated increases in P-glycoprotein activity independent of transporter protein expression. This work describes how C1P activates a signaling cascade to dynamically regulate P-glycoprotein transport at the BBB and offers potential clinical targets to modulate neuroprotection and drug delivery to the CNS.
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Affiliation(s)
- Emily V Mesev
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - David S Miller
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
| | - Ronald E Cannon
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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Garcia‐Gil M, Pierucci F, Vestri A, Meacci E. Crosstalk between sphingolipids and vitamin D3: potential role in the nervous system. Br J Pharmacol 2017; 174:605-627. [PMID: 28127747 PMCID: PMC6398521 DOI: 10.1111/bph.13726] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/16/2016] [Accepted: 01/18/2017] [Indexed: 12/14/2022] Open
Abstract
Sphingolipids are both structural and bioactive compounds. In particular, ceramide and sphingosine 1-phosphate regulate cell fate, inflammation and excitability. 1-α,25-dihydroxyvitamin D3 (1,25(OH)2 D3 ) is known to play an important physiological role in growth and differentiation in a variety of cell types, including neural cells, through genomic actions mediated by its specific receptor, and non-genomic effects that result in the activation of specific signalling pathways. 1,25(OH)2 D3 and sphingolipids, in particular sphingosine 1-phosphate, share many common effectors, including calcium regulation, growth factors and inflammatory cytokines, but it is still not known whether they can act synergistically. Alterations in the signalling and concentrations of sphingolipids and 1,25(OH)2 D3 have been found in neurodegenerative diseases and fingolimod, a structural analogue of sphingosine, has been approved for the treatment of multiple sclerosis. This review, after a brief description of the role of sphingolipids and 1,25(OH)2 D3 , will focus on the potential crosstalk between sphingolipids and 1,25(OH)2 D3 in neural cells.
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Affiliation(s)
- Mercedes Garcia‐Gil
- Department of BiologyUniversity of PisaPisaItaly
- Interdepartmental Research Center Nutrafood ‘Nutraceuticals and Food for Health’University of PisaPisaItaly
| | - Federica Pierucci
- Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, Molecular and Applied Biology Research UnitUniversity of FlorenceFlorenceItaly
- Interuniversitary Miology InstitutesItaly
| | - Ambra Vestri
- Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, Molecular and Applied Biology Research UnitUniversity of FlorenceFlorenceItaly
- Interuniversitary Miology InstitutesItaly
| | - Elisabetta Meacci
- Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, Molecular and Applied Biology Research UnitUniversity of FlorenceFlorenceItaly
- Interuniversitary Miology InstitutesItaly
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Ogle ME, Olingy CE, Awojoodu AO, Das A, Ortiz RA, Cheung HY, Botchwey EA. Sphingosine-1-Phosphate Receptor-3 Supports Hematopoietic Stem and Progenitor Cell Residence Within the Bone Marrow Niche. Stem Cells 2017; 35:1040-1052. [PMID: 28026131 DOI: 10.1002/stem.2556] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 11/19/2016] [Accepted: 12/08/2016] [Indexed: 12/29/2022]
Abstract
Hematopoietic stem and progenitor cells (HSPCs) egress from bone marrow (BM) during homeostasis and at increased rates during stress; however, the mechanisms regulating their trafficking remain incompletely understood. Here we describe a novel role for lipid receptor, sphingosine-1-phosphate receptor 3 (S1PR3), in HSPC residence within the BM niche. HSPCs expressed increased levels of S1PR3 compared to differentiated BM cells. Pharmacological antagonism or knockout (KO) of S1PR3 mobilized HSPCs into blood circulation, suggesting that S1PR3 influences niche localization. S1PR3 antagonism suppressed BM and plasma SDF-1, enabling HSPCs to migrate toward S1P-rich plasma. Mobilization synergized with AMD3100-mediated antagonism of CXCR4, which tethers HSPCs in the niche, and recovered homing deficits of AMD3100-treated grafts. S1PR3 antagonism combined with AMD3100 improved re-engraftment and survival in lethally irradiated recipients. Our studies indicate that S1PR3 and CXCR4 signaling cooperate to maintain HSPCs within the niche under homeostasis. These results highlight an important role for S1PR3 in HSPC niche occupancy and trafficking that can be harnessed for both rapid clinical stem cell mobilization and re-engraftment strategies, as well as the opportunity to design novel therapeutics for control of recruitment, homing, and localization through bioactive lipid signaling. Stem Cells 2017;35:1040-1052.
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Affiliation(s)
- Molly E Ogle
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA
| | - Claire E Olingy
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA
| | - Anthony O Awojoodu
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.,Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
| | - Anusuya Das
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
| | - Rafael A Ortiz
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA
| | - Hoi Yin Cheung
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA
| | - Edward A Botchwey
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.,Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
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Ordoñez M, Rivera IG, Presa N, Gomez-Muñoz A. Implication of matrix metalloproteinases 2 and 9 in ceramide 1-phosphate-stimulated macrophage migration. Cell Signal 2016; 28:1066-74. [DOI: 10.1016/j.cellsig.2016.05.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 05/05/2016] [Accepted: 05/05/2016] [Indexed: 01/08/2023]
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Presa N, Gomez-Larrauri A, Rivera IG, Ordoñez M, Trueba M, Gomez-Muñoz A. Regulation of cell migration and inflammation by ceramide 1-phosphate. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:402-9. [DOI: 10.1016/j.bbalip.2016.02.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 02/05/2016] [Accepted: 02/08/2016] [Indexed: 12/13/2022]
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Marycz K, Śmieszek A, Jeleń M, Chrząstek K, Grzesiak J, Meissner J. The effect of the bioactive sphingolipids S1P and C1P on multipotent stromal cells--new opportunities in regenerative medicine. Cell Mol Biol Lett 2016; 20:510-33. [PMID: 26110483 DOI: 10.1515/cmble-2015-0029] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 06/12/2015] [Indexed: 12/18/2022] Open
Abstract
Sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) belong to a family of bioactive sphingolipids that act as important extracellular signaling molecules and chemoattractants. This study investigated the influence of S1P and C1P on the morphology, proliferation activity and osteogenic properties of rat multipotent stromal cells derived from bone marrow (BMSCs) and subcutaneous adipose tissue (ASCs). We show that S1P and C1P can influence mesenchymal stem cells (MSCs), each in a different manner. S1P stimulation promoted the formation of cellular aggregates of BMSCs and ASCs, while C1P had an effect on the regular growth pattern and expanded intercellular connections, thereby increasing the proliferative activity. Although osteogenic differentiation of MSCs was enhanced by the addition of S1P, the effectiveness of osteoblast differentiation was more evident in BMSCs, particularly when biochemical and molecular marker levels were considered. The results of the functional osteogenic differentiation assay, which includes an evaluation of the efficiency of extracellular matrix mineralization (SEM-EDX), revealed the formation of numerous mineral aggregates in BMSC cultures stimulated with S1P. Our data demonstrated that in an appropriate combination, the bioactive sphingolipids S1P and C1P may find wide application in regenerative medicine, particularly in bone regeneration with the use of MSCs.
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