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1
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Wang B, Wu X, Cheng J, Ye J, Zhu H, Liu X. Regulatory role of S1P and its receptors in sepsis-induced liver injury. Front Immunol 2025; 16:1489015. [PMID: 39935473 PMCID: PMC11811114 DOI: 10.3389/fimmu.2025.1489015] [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: 08/31/2024] [Accepted: 01/13/2025] [Indexed: 02/13/2025] Open
Abstract
As an immune and metabolic organ, the liver affects the progression and prognosis of sepsis. Despite the severe adverse effects of sepsis liver injury on the body, treatment options remain limited. Sphingosine-1-phosphate (S1P) is a widely distributed lipid signaling molecule that binds to five sphingosine-1-phosphate receptors (S1PR) to regulate downstream signaling pathways involved in the pathophysiological processes of sepsis, including endothelial permeability, cytokine release, and vascular tone. This review summarizes current research on the role of S1P in normal liver biology and describes the mechanisms by which changes in S1P/S1PR affect the development of liver-related diseases. At the same time, the pathological processes underlying liver injury, as evidenced by clinical manifestations during sepsis, were comprehensively reviewed. This paper focused on the mechanistic pathways through which S1P and its receptors modulate immunity, bile acid metabolism, and liver-intestinal circulation in septic liver injury. Finally, the relationships between S1P and its receptors with liver inflammation and metabolism and the use of related drugs for the treatment of liver injury were examined. By elucidating the role of S1P and its receptor in the pathogenesis of sepsis liver injury, this review established a molecular targeting framework, providing novel insights into clinical and drug development.
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Affiliation(s)
- Bin Wang
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiaoyu Wu
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Jiangfeng Cheng
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Junming Ye
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
- Clinical College, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
| | - Hongquan Zhu
- Department of Critical Care Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Critical Care Medicine, The First Affiliated hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xiaofeng Liu
- Clinical College, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China
- Department of Emergency, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
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2
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Liu Y, Zheng J, He Q, Zhang H, Wen P, Wen P, Ge J, Yang Y, Zhang T, Wang R. Impact of varied immunosuppressive agents and posttransplant diabetes mellitus on prognosis among diverse transplant recipients (Experimental studies). Int J Surg 2024; 110:01279778-990000000-01056. [PMID: 38349011 PMCID: PMC11020014 DOI: 10.1097/js9.0000000000001135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 01/24/2024] [Indexed: 04/18/2024]
Abstract
The success of solid organ transplantation (SOT) and the use of immunosuppressive agents offer hope to patients with end-stage diseases. However, the impact of posttransplant diabetes mellitus (PTDM) on SOT patients has become increasingly evident. In our study, we utilized the Scientific Registry of Transplant Recipients (SRTR) database to investigate the association between PTDM and patient survival in various types of organ transplantations, including liver, kidney, intestinal, heart, lung, and combined heart-lung transplantations (all P<0.001). Our findings revealed a negative effect of PTDM on the survival of these patients. Furthermore, we examined the effects of both generic and innovator immunosuppressive agents on the development of PTDM and the overall survival of different SOT populations. Interestingly, the results were inconsistent, indicating that the impact of these agents may vary depending on the specific type of transplantation and patient population. Overall, our study provides a comprehensive and systematic assessment of the effects of different immunosuppressive agents on prognosis, as well as the impact of PTDM on the survival of patients undergoing various types of SOT. These findings emphasize the need for further research and highlight the importance of optimizing immunosuppressive regimens and managing PTDM in SOT patients to improve their long-term outcomes.
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Affiliation(s)
- Yuan Liu
- Department of Liver Transplantation, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinxin Zheng
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai, China
| | - Qining He
- Department of Liver Transplantation, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haijiao Zhang
- Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Peizhen Wen
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, China
| | - Peihao Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jifu Ge
- Department of Kidney Transplantation, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yang Yang
- School of Public Health, Imperial College London, South Kensington Campus, London SW72AZ, United Kingdom
| | - Tao Zhang
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Rangrang Wang
- Huadong Hospital Affiliated to Fudan University, Shanghai, China
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3
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Rigo F, De Stefano N, Patrono D, De Donato V, Campi L, Turturica D, Doria T, Sciannameo V, Berchialla P, Tandoi F, Romagnoli R. Impact of Hypothermic Oxygenated Machine Perfusion on Hepatocellular Carcinoma Recurrence after Liver Transplantation. J Pers Med 2023; 13:jpm13050703. [PMID: 37240873 DOI: 10.3390/jpm13050703] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/16/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND Machine perfusion may be able to mitigate ischemia-reperfusion injury (IRI), which increases hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). This study aimed to investigate the impact of dual-hypothermic oxygenated machine perfusion (D-HOPE) on HCC recurrence in LT. METHODS A single-center retrospective study was conducted from 2016 to 2020. Pre- and postoperative data of HCC patients undergoing LT were analyzed. Recipients of a D-HOPE-treated graft were compared to those of livers preserved using static cold storage (SCS). The primary endpoint was recurrence-free survival (RFS). RESULTS Of 326 patients, 246 received an SCS-preserved liver and 80 received a D-HOPE-treated graft (donation after brain death (DBD), n = 66; donation after circulatory death (DCD), n = 14). Donors of D-HOPE-treated grafts were older and had higher BMI. All DCD donors were treated by normothermic regional perfusion and D-HOPE. The groups were comparable in terms of HCC features and estimated 5-year RFS according to the Metroticket 2.0 model. D-HOPE did not reduce HCC recurrence (D-HOPE 10%; SCS 8.9%; p = 0.95), which was confirmed using Bayesian model averaging and inverse probability of treatment weighting-adjusted RFS analysis. Postoperative outcomes were comparable between groups, except for lower AST and ALT peak in the D-HOPE group. CONCLUSIONS In this single-center study, D-HOPE did not reduce HCC recurrence but allowed utilizing livers from extended criteria donors with comparable outcomes, improving access to LT for patients suffering from HCC.
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Affiliation(s)
- Federica Rigo
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Nicola De Stefano
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Damiano Patrono
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Victor De Donato
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Ludovico Campi
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Diana Turturica
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Teresa Doria
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Veronica Sciannameo
- Centre for Biostatistics, Epidemiology and Public Health (C-BEPH), Department of Clinical and Biological Sciences, University of Torino, 10126 Turin, Italy
| | - Paola Berchialla
- Centre for Biostatistics, Epidemiology and Public Health (C-BEPH), Department of Clinical and Biological Sciences, University of Torino, 10126 Turin, Italy
| | - Francesco Tandoi
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
- HPB and Liver Transplant Unit, Azienda Ospedaliero Universitaria Consorziale Policlinico, 70124 Bari, Italy
| | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, 10126 Turin, Italy
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Paul B, Lewinska M, Andersen JB. Lipid alterations in chronic liver disease and liver cancer. JHEP Rep 2022; 4:100479. [PMID: 35469167 PMCID: PMC9034302 DOI: 10.1016/j.jhepr.2022.100479] [Citation(s) in RCA: 136] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well as in the onset, progression, and maintenance of cancers. Fatty acids and cholesterol are the building blocks of lipids, orchestrating these crucial metabolic processes. In the liver, lipid alterations are prevalent as a cause and consequence of chronic hepatitis B and C virus infections, alcoholic hepatitis, and non-alcoholic fatty liver disease and steatohepatitis. Recent developments in lipidomics have also revealed that dynamic changes in triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol are involved in the development and progression of primary liver cancer. Accordingly, the transcriptional landscape of lipid metabolism suggests a carcinogenic role of increasing fatty acids and sterol synthesis. However, limited mechanistic insights into the complex nature of the hepatic lipidome have so far hindered the development of effective therapies.
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5
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Ceramide Metabolism Enzymes-Therapeutic Targets against Cancer. ACTA ACUST UNITED AC 2021; 57:medicina57070729. [PMID: 34357010 PMCID: PMC8303233 DOI: 10.3390/medicina57070729] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 07/07/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022]
Abstract
Sphingolipids are both structural molecules that are essential for cell architecture and second messengers that are involved in numerous cell functions. Ceramide is the central hub of sphingolipid metabolism. In addition to being the precursor of complex sphingolipids, ceramides induce cell cycle arrest and promote cell death and inflammation. At least some of the enzymes involved in the regulation of sphingolipid metabolism are altered in carcinogenesis, and some are targets for anticancer drugs. A number of scientific reports have shown how alterations in sphingolipid pools can affect cell proliferation, survival and migration. Determination of sphingolipid levels and the regulation of the enzymes that are implicated in their metabolism is a key factor for developing novel therapeutic strategies or improving conventional therapies. The present review highlights the importance of bioactive sphingolipids and their regulatory enzymes as targets for therapeutic interventions with especial emphasis in carcinogenesis and cancer dissemination.
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6
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Grbčić P, Sedić M. Sphingosine 1-Phosphate Signaling and Metabolism in Chemoprevention and Chemoresistance in Colon Cancer. Molecules 2020; 25:E2436. [PMID: 32456134 PMCID: PMC7287727 DOI: 10.3390/molecules25102436] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/08/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023] Open
Abstract
Colorectal carcinoma (CRC) is the leading cause of cancer-related deaths worldwide. Despite advances in prevention and treatment modalities for CRC, rapidly developing resistance to chemotherapy limits its effectiveness. For that reason, it is important to better understand the mechanisms that undergird the process of chemoresistance to enable design of novel anticancer agents specifically targeting malignant properties of cancer cells. Over recent decades, bioactive sphingolipid species have come under the spotlight for their recognized role in cancer development and progression, and the evidence has surfaced to support their role as regulators of anti-cancer drug resistance. Colon cancer is characterized by a shift in sphingolipid balance that favors the production and accumulation of oncogenic species such as sphingosine 1-phosphate (S1P). S1P is known to govern the processes that facilitate cancer cell growth and progression including proliferation, survival, migration, invasion and inflammation. In this review paper, we will give a comprehensive overview of current literature findings on the molecular mechanisms by which S1P turnover, transport and signaling via receptor-dependent and independent pathways shape colon cancer cell behavior and influence treatment outcome in colon cancer. Combining available modulators of S1P metabolism and signaling with standard chemotherapy drugs could provide a rational approach to achieve enhanced therapeutic response, diminish chemoresistance development and improve the survival outcome in CRC patients.
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Affiliation(s)
| | - Mirela Sedić
- Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia;
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7
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Abstract
Sphingosine-1-phosphate (S1P) can regulate several physiological and pathological processes. S1P signaling via its cell surface receptor S1PR1 has been shown to enhance tumorigenesis and stimulate growth, expansion, angiogenesis, metastasis, and survival of cancer cells. S1PR1-mediated tumorigenesis is supported and amplified by activation of downstream effectors including STAT3, interleukin-6, and NF-κB networks. S1PR1 signaling can also trigger various other signaling pathways involved in carcinogenesis including activation of PI3K/AKT, MAPK/ERK1/2, Rac, and PKC/Ca, as well as suppression of cyclic adenosine monophosphate (cAMP). It also induces immunological tolerance in the tumor microenvironment, while the immunosuppressive function of S1PR1 can also lead to the generation of pre-metastatic niches. Some tumor cells upregulate S1PR1 signaling pathways, which leads to drug resistant cancer cells, mainly through activation of STAT3. This signaling pathway is also implicated in some inflammatory conditions leading to the instigation of inflammation-driven cancers. Furthermore, it can also increase survival via induction of anti-apoptotic pathways, for instance, in breast cancer cells. Therefore, S1PR1 and its signaling pathways can be considered as potential anti-tumor therapeutic targets, alone or in combination therapies. Given the oncogenic nature of S1PR1 and its distribution in a variety of cancer cell types along with its targeting advantages over other molecules of this family, S1PR1 should be considered a favorable target in therapeutic approaches to cancer. This review describes the role of S1PR1 in cancer development and progression, specifically addressing breast cancer, glioma, and hematopoietic malignancies. We also discuss the potential use of S1P signaling modulators as therapeutic targets in cancer therapy.
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8
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Maceyka M, Rohrbach T, Milstien S, Spiegel S. Role of Sphingosine Kinase 1 and Sphingosine-1-Phosphate Axis in Hepatocellular Carcinoma. Handb Exp Pharmacol 2019; 259:3-17. [PMID: 31321542 DOI: 10.1007/164_2019_217] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is primarily diagnosed in the latter stages of disease progression and is the third leading cause of cancer deaths worldwide. Thus, there is a need to find biomarkers of early HCC as well as the development of more effective treatments for the disease. Sphingosine-1-phosphate (S1P) is a pleiotropic lipid signaling molecule produced by two isoforms of sphingosine kinase (SphK1 and SphK2) that is involved in regulation of many aspects of mammalian physiology and pathophysiology, including inflammation, epithelial and endothelial barrier function, cancer, and metastasis, among many others. Abundant evidence indicates that SphK1 and S1P promote cancer progression and metastasis in multiple types of cancers. However, the role of SphK/S1P in HCC is less well studied. Here, we review the current state of knowledge of SphKs and S1P in HCC, including evidence for the correlation of SphK1 expression and S1P levels with progression of HCC and negative outcomes, and discuss how this information could lead to the design of more effective diagnostic and treatment modalities for HCC.
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Affiliation(s)
- Michael Maceyka
- Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Timothy Rohrbach
- Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Sheldon Milstien
- Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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Matsushima-Nishiwaki R, Yamada N, Fukuchi K, Kozawa O. Sphingosine 1-phosphate (S1P) reduces hepatocyte growth factor-induced migration of hepatocellular carcinoma cells via S1P receptor 2. PLoS One 2018; 13:e0209050. [PMID: 30543684 PMCID: PMC6292590 DOI: 10.1371/journal.pone.0209050] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 11/27/2018] [Indexed: 12/12/2022] Open
Abstract
A bioactive lipid, sphingosine 1-phosphate (S1P), acts extracellularly as a potent mediator, and is implicated in the progression of various cancers including hepatocellular carcinoma (HCC). S1P exerts its functions by binding to five types of specific receptors, S1P receptor 1 (S1PR1), S1PR2, S1PR3, S1PR4 and S1PR5 on the plasma membrane. However, the exact roles of S1P and each S1PR in HCC cells remain to be clarified. In the present study, we investigated the effect of S1P on the hepatocyte growth factor (HGF)-induced migration of human HCC-derived HuH7 cells, and the involvement of each S1PR. S1P dose-dependently reduced the HGF-induced migration of HuH7 cells. We found that all S1PRs exist in the HuH7 cells. Among each selective agonist for five S1PRs, CYM5520, a selective S1PR2 agonist, significantly suppressed the HGF-induced HuH7 cell migration whereas selective agonists for S1PR1, S1PR3, S1PR4 or S1PR5 failed to affect the migration. The reduction of the HGF-induced migration by S1P was markedly reversed by treatment of JTE013, a selective antagonist for S1PR2, and S1PR2- siRNA. These results strongly suggest that S1P reduces the HGF-induced HCC cell migration via S1PR2. Our findings may provide a novel potential of S1PR2 to therapeutic strategy for metastasis of HCC.
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Affiliation(s)
| | - Noriko Yamada
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Kouki Fukuchi
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Osamu Kozawa
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
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10
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a group of liver disorders encompassing simple hepatic steatosis and its more aggressive forms of nonalcoholic steatohepatitis and cirrhosis. It is a rapidly growing health concern and the major cause for the increasing incidence of primary liver tumors. Unequivocal evidence shows that sphingolipid metabolism is altered in the course of the disease and these changes might contribute to NAFLD progression. Recent data provide solid support to the notion that deregulated ceramide and sphingosine-1-phosphate metabolism are present at all stages of NAFLD, i.e., steatosis, nonalcoholic steatohepatitis, advanced fibrosis, and hepatocellular carcinoma (HCC). Insulin sensitivity, de novo lipogenesis, and the resulting lipotoxicity, fibrosis, and angiogenesis are all seemingly regulated in a manner that involves either ceramide and/or sphingosine-1-phosphate. Sphingolipids might also participate in the onset of hepatocellular senescence. The latter has been shown to contribute to the advancement of cirrhosis to HCC in the classical cases of end-stage liver disease, i.e., viral- or alcohol-induced; however, emerging evidence suggests that senescence is also involved in the pathogenicity of NAFLD possibly via changes in ceramide metabolism.
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White C, Alshaker H, Cooper C, Winkler M, Pchejetski D. The emerging role of FTY720 (Fingolimod) in cancer treatment. Oncotarget 2018; 7:23106-27. [PMID: 27036015 PMCID: PMC5029614 DOI: 10.18632/oncotarget.7145] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 01/19/2016] [Indexed: 02/07/2023] Open
Abstract
FTY720 (Fingolimod) is a clinically approved immunomodulating therapy for multiple sclerosis that sequesters T-cells to lymph nodes through functional antagonism of sphingosine-1-phosphate 1 receptor. FTY720 also demonstrates a proven efficacy in multiple in vitro and in vivo cancer models, suggesting a potential therapeutic role in cancer patients. A potential anticancer mechanism of FTY720 is through the inhibition of sphingosine kinase 1, a proto-oncogene with in vitro and clinical cancer association. In addition, FTY720's anticancer properties may be attributable to actions on several other molecular targets. This study focuses on reviewing the emerging evidence regarding the anticancer properties and molecular targets of FTY720. While the clinical transition of FTY720 is currently limited by its immune suppression effects, studies aiming at FTY720 delivery and release together with identifying its key synergetic combinations and relevant patient subsets may lead to its rapid introduction into the clinic.
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Affiliation(s)
| | - Heba Alshaker
- Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan.,School of Medicine, University of East Anglia, Norwich, UK
| | - Colin Cooper
- School of Medicine, University of East Anglia, Norwich, UK
| | - Matthias Winkler
- Department of Surgery and Cancer, Imperial College London, London, UK
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12
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Sphingosine 1-phosphate regulates proliferation, cell cycle and apoptosis of hepatocellular carcinoma cells via syndecan-1. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2017; 148:32-38. [PMID: 29180036 DOI: 10.1016/j.pbiomolbio.2017.11.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 11/05/2017] [Accepted: 11/23/2017] [Indexed: 02/05/2023]
Abstract
Sphingosine 1-phosphate (S1P) plays an important role in hepatocarcinogenesis. We previously demonstrated that S1P induced epithelial-mesenchymal transition of hepatocellular carcinoma (HCC) cells via an MMP-7/Syndecan-1/TGF-β autocrine loop. In the present study, we investigated the regulative role of S1P in cell survival and progression of HCC cells, and tested whether syndecan-1 is required in the S1P action. After transfected with syndecan-1 shRNA, HepG2 and SMMC7721 cells were treated with S1P for 72 h, and then cell proliferation was detected by CCK8 assay, and cell cycle progression and cell apoptosis were detected by flow cytometry. The levels of apoptosis markers including cleaved-Caspase-3 and cleaved-PARP in SMMC7721 cells were examined by western blotting. Results showed that S1P significantly enhanced cell proliferation in HCC cells, which was significantly inhibited by syndecan-1 shRNA. S1P induced the cell proportion in S phase in HCC cells, whereas S1P decreased the proportion of cells in both early and late apoptosis. Syndecan-1 shRNA induced the G2/M arrest in the presence of S1P. In the syndecan-1 shRNA transfected HCC cells, the proportions of late and early apoptotic cells, and levels of cleaved-Caspase-3 and cleaved-PARP were significantly increased in cells with or without S1P treatment. Thus, S1P augments the proportion of cells in S phase of the cell cycle that might translate to enhance HCC cell proliferation and inhibit the cell apoptosis via syndecan-1.
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13
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Ahmed D, de Verdier PJ, Ryk C, Lunqe O, Stål P, Flygare J. FTY720 (Fingolimod) sensitizes hepatocellular carcinoma cells to sorafenib-mediated cytotoxicity. Pharmacol Res Perspect 2015; 3:e00171. [PMID: 26516583 PMCID: PMC4618642 DOI: 10.1002/prp2.171] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 06/26/2015] [Accepted: 06/27/2015] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. The multityrosine kinase inhibitor sorafenib is used in the therapy of advanced disease. However, the effects of sorafenib are limited, and combination treatments aiming at improved survival are encouraged. The sphingosine analog FTY720 (Fingolimod), which is approved for treatment of multiple sclerosis, has shown tumor suppressive effects in cell lines and animal models of HCC. In the present study, we combined sorafenib with FTY720 in order to sensitize the HCC cell lines Huh7 and HepG2 to sorafenib treatment. Using the XTT assay we show that noncytotoxic doses of FTY720 synergistically enhanced the decrease in viability caused by treatment of both cell lines with increasing doses of sorafenib. Further studies in Huh7 revealed that combined treatment with FTY720 and sorafenib resulted in G1 arrest and enhanced cell death measured using flow cytometry analysis of cells labeled with propidium iodide (PI)/Annexin-V and PI and 4′,6-diamidino-2-phenylindole-staining of nuclei. In addition, signs of both caspase-dependent and – independent apoptosis were observed, as cotreatment with FTY720 and sorafenib caused cytochrome c release and poly-ADP ribose polymerase-cleavage as well as translocation of Apoptosis-inducing factor into the cytosol. We also detected features of autophagy blockage, as the protein levels of LC3-II and p62 were affected by combined treatment with FTY720 and sorafenib. Together, our results suggest that FTY720 sensitizes HCC cells to cytotoxic effects induced by treatment with sorafenib alone. These findings warrant further investigations of combined treatment with sorafenib and FTY720 in vivo in order to develop more effective treatment of HCC.
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Affiliation(s)
- Dilruba Ahmed
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden
| | - Petra J de Verdier
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden
| | - Charlotta Ryk
- Urology Laboratory, Department of Molecular Medicine and Surgery, Karolinska Institutet 171 76, Stockholm, Sweden
| | - Oscar Lunqe
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden
| | - Per Stål
- Division of Gastroenterology and Hepatology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge Stockholm, Sweden
| | - Jenny Flygare
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet Huddinge, Stockholm, Sweden
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14
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Patmanathan SN, Yap LF, Murray PG, Paterson IC. The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod. J Cell Mol Med 2015; 19:2329-40. [PMID: 26171944 PMCID: PMC4594675 DOI: 10.1111/jcmm.12635] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 05/20/2015] [Indexed: 12/20/2022] Open
Abstract
Almost all drugs approved for use in humans possess potentially beneficial 'off-target' effects in addition to their principal activity. In some cases this has allowed for the relatively rapid repurposing of drugs for other indications. In this review we focus on the potential for re-purposing FTY720 (also known as fingolimod, Gilenya(™)), an immunomodulatory drug recently approved for the treatment of multiple sclerosis (MS). The therapeutic benefit of FTY720 in MS is largely attributed to the immunosuppressive effects that result from its modulation of sphingosine 1-phosphate receptor signalling. However, this drug has also been shown to inhibit other cancer-associated signal transduction pathways in part because of its structural similarity to sphingosine, and consequently shows efficacy as an anti-cancer agent both in vitro and in vivo. Here, we review the effects of FTY720 on signal transduction pathways and cancer-related cellular processes, and discuss its potential use as an anti-cancer drug.
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Affiliation(s)
- Sathya Narayanan Patmanathan
- Department of Oral Biology and Biomedical Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Lee Fah Yap
- Department of Oral Biology and Biomedical Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Paul G Murray
- School of Cancer Sciences, University of Birmingham, Birmingham, UK
| | - Ian C Paterson
- Department of Oral Biology and Biomedical Sciences and Oral Cancer Research & Coordinating Centre, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
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15
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Raza A, Huang WC, Takabe K. Advances in the management of peritoneal mesothelioma. World J Gastroenterol 2014; 20:11700-11712. [PMID: 25206274 PMCID: PMC4155360 DOI: 10.3748/wjg.v20.i33.11700] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2013] [Revised: 03/21/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
Malignant peritoneal mesothelioma (PM) is an infrequent disease which has historically been associated with a poor prognosis. Given its long latency period and non-specific symptomatology, a diagnosis of PM can be suggested by occupational exposure history, but ultimately relies heavily on imaging and diagnostic biopsy. Early treatment options including palliative operative debulking, intraperitoneal chemotherapy, and systemic chemotherapy have marginally improved the natural course of the disease with median survival being approximately one year. The advent of cytoreduction (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has dramatically improved survival outcomes with wide median survival estimates between 2.5 to 9 years; these studies however remain largely heterogeneous, with differing study populations, tumor biology, and specific treatment regimens. More recent investigations have explored extent of cytoreduction, repeated operative intervention, and choice of chemotherapy but have been unable to offer definitive conclusions. CRS and HIPEC remain morbid procedures with complication rates ranging between 30% to 46% in larger series. Accordingly, an increasing interest in identifying molecular targets and developing targeted therapies is emerging. Among such novel targets is sphingosine kinase 1 (SphK1) which regulates the production of sphingosine-1-phosphate, a biologically active lipid implicated in various cancers including malignant mesothelioma. The known action of specific SphK inhibitors may warrant further exploration in peritoneal disease.
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16
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Maroni L, Alpini G, Marzioni M. Cholangiocarcinoma development: the resurgence of bile acids. Hepatology 2014; 60:795-7. [PMID: 24828905 DOI: 10.1002/hep.27223] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 05/07/2014] [Accepted: 05/10/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Luca Maroni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy
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17
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Alshaker H, Sauer L, Monteil D, Ottaviani S, Srivats S, Böhler T, Pchejetski D. Therapeutic potential of targeting SK1 in human cancers. Adv Cancer Res 2013; 117:143-200. [PMID: 23290780 DOI: 10.1016/b978-0-12-394274-6.00006-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Sphingosine kinase 1 (SK1) is a lipid enzyme with oncogenic properties that converts the proapoptotic lipids ceramide and sphingosine into the antiapoptotic lipid sphingosine-1-phosphate and activates the signal transduction pathways that lead to cell proliferation, migration, the activation of the inflammatory response, and the impairment of apoptosis. There is compelling evidence that SK1 activation contributes to cancer progression leading to increased oncogenic transformation, tumor growth, resistance to therapies, tumor neovascularization, and metastatic spread. High levels of SK1 expression or activity have been associated with a poor prognosis in several human cancers. Recent studies using cancer cell and mouse models demonstrate a significant potential for SK1-targeting therapies to synergize with the effects of chemotherapy and radiotherapy; however, until recently the absence of clinically applicable SK1 inhibitors has limited the translation of these findings into patients. With the recent discovery of SK1 inhibiting properties of a clinically approved drug FTY720 (Fingolimod), SK1 has gained significant attention from both clinicians and the pharmaceutical industry and it is hoped that trials of newly developed SK1 inhibitors may follow soon. This review provides an overview of the SK1 signaling, its relevance to cancer progression, and the potential clinical significance of targeting SK1 for improved local or systemic control of human cancers.
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Affiliation(s)
- Heba Alshaker
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom
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18
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Skill N, Wu J, Xu Y, Zhao Z, Maluccio M. Lysophosphatidic acid aberrancies and hepatocellular carcinoma: studies in the MDR2 gene knockout mouse. Cancer Invest 2013; 31:145-55. [PMID: 23362952 DOI: 10.3109/07357907.2012.762779] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Studies show that lysophosphatidic acid (LPA) reprogramming is associated with the development of hepatocellular carcinoma (HCC). This manuscript evaluates the MDR2(-/-) model of HCC as a tool to examine the role of LPA reprogramming in the initiation/progression of HCC and identify novel treatment targets. Hepatic tumors developed in MDR2(-/-) mice between 9-12 m and serum LPA levels were greater in MDR2(-/-) when compared to controls. Blocking LPA biosynthesis/signaling significantly reduced tumor burden. LPA biosynthesis/signaling plays an important role in murine MDR2(-/-) model and is potentially linked to regulation of TNFα or other cytokines that are relevant to high-risk patients.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/deficiency
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- Animals
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Drug Resistance, Multiple
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms, Experimental/blood
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Lysophospholipids/blood
- Lysophospholipids/genetics
- Lysophospholipids/metabolism
- Mice
- Mice, Knockout
- Phosphodiesterase Inhibitors/pharmacology
- Phospholipids/metabolism
- Phosphoric Diester Hydrolases/metabolism
- Receptors, Lysosphingolipid/antagonists & inhibitors
- Receptors, Lysosphingolipid/metabolism
- Signal Transduction/drug effects
- ATP-Binding Cassette Sub-Family B Member 4
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Affiliation(s)
- Nicholas Skill
- Department of Surgery, Indiana University, Indianapolis, IN, USA.
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19
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Kuroda S, Tashiro H, Igarashi Y, Tanimoto Y, Nambu J, Oshita A, Kobayashi T, Amano H, Tanaka Y, Ohdan H. Rho inhibitor prevents ischemia-reperfusion injury in rat steatotic liver. J Hepatol 2012; 56:146-52. [PMID: 21756846 DOI: 10.1016/j.jhep.2011.04.029] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Revised: 04/07/2011] [Accepted: 04/29/2011] [Indexed: 01/22/2023]
Abstract
BACKGROUND & AIMS Hepatic stellate cells are thought to play a role in modulating intrahepatic vascular resistance based on their capacity to contract via Rho signaling. We investigated the effect of a Rho-kinase inhibitor on ischemia-reperfusion injury in the steatotic liver. METHODS Steatotic livers, induced by a choline-deficient diet in rats, were subjected to ischemia-reperfusion injury. Hepatic stellate cells isolated from steatotic livers were analyzed for contractility and Rho signaling activity. The portal pressure of the perfused rat liver and the survival rate after ischemia-reperfusion were also investigated. RESULTS Hepatic stellate cells from steatotic livers showed increased contractility and upregulation of Rho-kinase 2 compared with those from normal livers. Furthermore, endothelin-1 significantly enhanced the contractility and phosphorylation level of myosin light chain and cofilin in hepatic stellate cells isolated from steatotic livers. A specific Rho-kinase inhibitor, fasudil, significantly suppressed the contractility and decreased the phosphorylation levels of myosin light chain and cofilin. Serum levels of endothelin-1 were markedly increased after IR in rats with steatotic livers, whereas fasudil significantly decreased endothelin-1 serum levels. Rats with steatotic livers showed a significant increase in portal perfusion pressure after ischemia-reperfusion and a significant decrease in survival rate; fasudil treatment significantly reduced these effects. CONCLUSIONS Activation of Rho/Rho-kinase signaling in hepatic stellate cells isolated from steatotic livers is associated with an increased susceptibility to ischemia-reperfusion injury. A Rho-kinase inhibitor attenuated the activation of hepatic stellate cells isolated from steatotic livers and improved ischemia-reperfusion injury in steatotic rats.
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Affiliation(s)
- Shintaro Kuroda
- Department of Surgery, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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Abstract
Sphingosine kinase 1 (SK1) is a lipid enzyme with oncogenic properties that converts the proapoptotic lipid sphingosine into the antiapoptotic lipid sphingosine-1-phosphate, which activates the signal transduction pathways that lead to cell proliferation, migration, activation of the inflammatory response and impairment of apoptosis. Compelling evidence suggests that SK1 activation contributes to cancer progression leading to increased oncogenic transformation, tumor growth, resistance to therapies, tumor neovascularization and metastatic spread. High levels of SK1 expression or activity have been associated with poor prognosis in several cancers, including those of the prostate. Recent studies using prostate cancer cell and mouse models demonstrate a significant potential for SK1-targeting therapies to synergize with the effects of docetaxel chemotherapy and radiotherapy. However, until recently the absence of clinically applicable SK1 inhibitors has limited the translation of these findings into patients. With the recent discovery that clinically approved drug fingolimod has SK1-inhibiting properties, SK1 has gained significant attention from both clinicians and the pharmaceutical industry and it is hoped that trials of newly developed SK1 inhibitors might follow soon.
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