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Future Oncology (London, England) Oct 2010Sphingolipids have emerged as bioeffector molecules, controlling various aspects of cell growth and proliferation in cancer, which is becoming the deadliest disease in... (Review)
Review
Sphingolipids have emerged as bioeffector molecules, controlling various aspects of cell growth and proliferation in cancer, which is becoming the deadliest disease in the world. These lipid molecules have also been implicated in the mechanism of action of cancer chemotherapeutics. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative responses, such as cell growth inhibition, apoptosis induction, senescence modulation, endoplasmic reticulum stress responses and/or autophagy. Interestingly, recent studies suggest de novo-generated ceramides may have distinct and opposing roles in the promotion/suppression of tumors, and that these activities are based on their fatty acid chain lengths, subcellular localization and/or direct downstream targets. For example, in head and neck cancer cells, ceramide synthase 6/C(16)-ceramide addiction was revealed, and this was associated with increased tumor growth, whereas downregulation of its synthesis resulted in ER stress-induced apoptosis. By contrast, ceramide synthase 1-generated C(18)-ceramide has been shown to suppress tumor growth in various cancer models, both in situ and in vivo. In addition, ceramide metabolism to generate sphingosine-1-phosphate (S1P) by sphingosine kinases 1 and 2 mediates, with or without the involvement of G-protein-coupled S1P receptor signaling, prosurvival, angiogenesis, metastasis and/or resistance to drug-induced apoptosis. Importantly, recent findings regarding the mechanisms by which sphingolipid metabolism and signaling regulate tumor growth and progression, such as identifying direct intracellular protein targets of sphingolipids, have been key for the development of new chemotherapeutic strategies. Thus, in this article, we will present conclusions of recent studies that describe opposing roles of de novo-generated ceramides by ceramide synthases and/or S1P in the regulation of cancer pathogenesis, as well as the development of sphingolipid-based cancer therapeutics and drug resistance.
Topics: Animals; Ceramides; Drug Resistance, Neoplasm; Humans; Lysophospholipids; Neoplasms; Sphingolipids; Sphingosine
PubMed: 21062159
DOI: 10.2217/fon.10.116 -
Journal of Lipid Research Apr 2009Lipid phosphate phosphatases (LPPs) regulate cell signaling by modifying the concentrations of lipid phosphates versus their dephosphorylated products. The ecto-activity... (Review)
Review
Lipid phosphate phosphatases (LPPs) regulate cell signaling by modifying the concentrations of lipid phosphates versus their dephosphorylated products. The ecto-activity regulates the availability of extracellular lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) and thereby signaling by their respective receptors. LPP products (monoacylglycerol or sphingosine) are taken up by cells and rephosphorylated to produce LPA and S1P, respectively, which activate intracellular signaling cascades. The proposed integrin binding domain on the external surface of LPP3 modifies cell/cell interactions. Expression of LPPs on internal membranes controls signaling depending on the access of lipid phosphates to their active sites. Different LPPs perform distinct functions, probably based on integrin binding, their locations, and their abilities to metabolize different lipid phosphates in vivo.
Topics: Animals; Extracellular Space; Humans; Intracellular Space; Lysophospholipids; Phosphatidate Phosphatase; Signal Transduction; Sphingosine
PubMed: 19066402
DOI: 10.1194/jlr.R800055-JLR200 -
Anti-cancer Agents in Medicinal... Nov 2011Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that regulates several processes important for hematologic cancer progression. S1P is generated... (Review)
Review
Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that regulates several processes important for hematologic cancer progression. S1P is generated by two sphingosine kinases, SphK1 and SphK2, and is exported outside the cell, where it activates specific cell surface S1P G-protein coupled receptors in autocrine/paracrine manner, coined "inside-out signaling". In this review, we highlight the importance of SphK1 and inside-out signaling by S1P in hematologic malignancy. We also summarize the results of studies targeting the SphK1/S1P/S1P receptor axis and the effects of the S1P receptor modulator, FTY720, in hematologic malignancy.
Topics: Animals; Fingolimod Hydrochloride; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Receptors, Lysosphingolipid; Sphingosine
PubMed: 21707492
DOI: 10.2174/187152011797655122 -
Biochimica Et Biophysica Acta Dec 2006Sphingolipids are ubiquitous components of cell membranes and their metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) have important... (Review)
Review
Sphingolipids are ubiquitous components of cell membranes and their metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) have important physiological functions, including regulation of cell growth and survival. Cer and Sph are associated with growth arrest and apoptosis. Many stress stimuli increase levels of Cer and Sph, whereas suppression of apoptosis is associated with increased intracellular levels of S1P. In addition, extracellular/secreted S1P regulates cellular processes by binding to five specific G protein coupled-receptors (GPCRs). S1P is generated by phosphorylation of Sph catalyzed by two isoforms of sphingosine kinases (SphK), type 1 and type 2, which are critical regulators of the "sphingolipid rheostat", producing pro-survival S1P and decreasing levels of pro-apoptotic Sph. Since sphingolipid metabolism is often dysregulated in many diseases, targeting SphKs is potentially clinically relevant. Here we review the growing recent literature on the regulation and the roles of SphKs and S1P in apoptosis and diseases.
Topics: Animals; Apoptosis; Disease; Enzyme Activation; Humans; Lysophospholipids; Phosphotransferases (Alcohol Group Acceptor); Sphingosine
PubMed: 16996023
DOI: 10.1016/j.bbamem.2006.08.007 -
Tissue Engineering. Part B, Reviews Dec 2015The presentation and controlled release of bioactive signals to direct cellular growth and differentiation represents a widely used strategy in tissue engineering.... (Review)
Review
The presentation and controlled release of bioactive signals to direct cellular growth and differentiation represents a widely used strategy in tissue engineering. Historically, work in this field has primarily focused on the delivery of large cytokines and growth factors, which can be costly to manufacture and difficult to deliver in a sustained manner. There has been a marked increase over the past decade in the pursuit of lipid mediators due to their wide range of effects over multiple cell types, low cost, and ease of scale-up. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are two bioactive lysophospholipids (LPLs) that have gained attention for use as pharmacological agents in tissue engineering applications. While these lipids can have similar effects on cellular response, they possess distinct chemical backbones, mechanisms of synthesis and degradation, and signaling pathways using a discrete set of G-protein-coupled receptors (GPCRs). LPA and S1P predominantly act extracellularly on their GPCRs and can directly regulate cell survival, differentiation, cytokine secretion, proliferation, and migration--each of the important functions that must be considered in regenerative medicine. In addition to these potent physiological functions, these LPLs play pivotal roles in a number of pathophysiological processes. To capitalize on the promise of these molecules in tissue engineering, these lipids have been incorporated into biomaterials for in vivo delivery. Here, we survey the effects of LPA and S1P on both cellular- and tissue-level phenotypes, with an eye toward regulating stem/progenitor cell growth and differentiation. In particular, we examine work that has translational applications for cell-based tissue engineering strategies in promoting cell survival, bone and cartilage engineering, and therapeutic angiogenesis.
Topics: Animals; Cell Differentiation; Cell Movement; Humans; Lysophospholipids; Receptors, G-Protein-Coupled; Sphingosine; Stem Cells; Tissue Engineering
PubMed: 26035484
DOI: 10.1089/ten.TEB.2015.0107 -
Trends in Endocrinology and Metabolism:... Nov 2016Sphingolipids (SL) are both fundamental structural components of the eukaryotic membranes and signaling molecules that regulate a variety of biological functions. The... (Review)
Review
Sphingolipids (SL) are both fundamental structural components of the eukaryotic membranes and signaling molecules that regulate a variety of biological functions. The highly-bioactive lipids, ceramide and sphingosine-1-phosphate, have emerged as important regulators of cardiovascular function in health and disease. In this review we discuss recent insights into the role of SLs, particularly ceramide and sphingosine-1-phosphate, in the pathophysiology of the cardiovascular system. We also highlight advances into the molecular mechanisms regulating serine palmitoyltransferase, the first and rate-limiting enzyme of de novo SL biosynthesis, with an emphasis on the recently discovered inhibitors of serine palmitoyltransferase, ORMDL and NOGO-B proteins. Understanding the molecular mechanisms regulating this biosynthetic pathway may lead to the development of novel therapeutic approaches for the treatment of cardiovascular diseases.
Topics: Animals; Cardiovascular Diseases; Homeostasis; Humans; Lysophospholipids; Nogo Proteins; Sphingolipids; Sphingosine
PubMed: 27562337
DOI: 10.1016/j.tem.2016.07.005 -
Reproductive Sciences (Thousand Oaks,... May 2014Sphingosine-1-phosphate (S1P) plays crucial roles in the regulation of cell growth, proliferation, differentiation, cell survival, migration, and angiogenesis. In the... (Review)
Review
Sphingosine-1-phosphate (S1P) plays crucial roles in the regulation of cell growth, proliferation, differentiation, cell survival, migration, and angiogenesis. In the reproductive system, S1P protects mammalian germ cells from irradiation or chemotherapy-induced cell death in vivo and in vitro. Moreover, S1P could improve the survival rate of thawed ovary and transplanted ovary. Furthermore, S1P could improve the developmental potential of oocyte and preimplantation embryo. In conclusion, S1P plays important roles in reproduction.
Topics: Animals; Blastocyst; Cell Differentiation; Female; Humans; Lysophospholipids; Male; Oocytes; Reproduction; Sphingosine
PubMed: 24336672
DOI: 10.1177/1933719113512534 -
FEBS Letters Oct 2002The sphingolipid metabolite sphingosine-1-phosphate (S1P) is a serum-borne lipid that regulates many vital cellular processes. S1P is the ligand of a family of five... (Review)
Review
The sphingolipid metabolite sphingosine-1-phosphate (S1P) is a serum-borne lipid that regulates many vital cellular processes. S1P is the ligand of a family of five specific G protein-coupled receptors that are differentially expressed in different tissues and regulate diverse cellular actions. Much less is known of the intracellular actions of S1P. It has been suggested that S1P may also function as an intracellular second messenger to regulate calcium mobilization, cell growth and suppression of apoptosis in response to a variety of extracellular stimuli. Dissecting the dual actions and identification of intracellular targets of S1P has been challenging, but there is ample evidence to suggest that the balance between S1P and ceramide and/or sphingosine levels in cells is an important determinant of cell fate.
Topics: Animals; Cell Division; Cell Survival; Enzyme Inhibitors; Humans; Lipid Metabolism; Lysophospholipids; Models, Biological; Signal Transduction; Sphingosine
PubMed: 12401202
DOI: 10.1016/s0014-5793(02)03480-4 -
Annual Review of Physiology Feb 2017Vertebrates are endowed with a closed circulatory system, the evolution of which required novel structural and regulatory changes. Furthermore, immune cell trafficking... (Review)
Review
Vertebrates are endowed with a closed circulatory system, the evolution of which required novel structural and regulatory changes. Furthermore, immune cell trafficking paradigms adapted to the barriers imposed by the closed circulatory system. How did such changes occur mechanistically? We propose that spatial compartmentalization of the lipid mediator sphingosine 1-phosphate (S1P) may be one such mechanism. In vertebrates, S1P is spatially compartmentalized in the blood and lymphatic circulation, thus comprising a sharp S1P gradient across the endothelial barrier. Circulatory S1P has critical roles in maturation and homeostasis of the vascular system as well as in immune cell trafficking. Physiological functions of S1P are tightly linked to shear stress, the key biophysical stimulus from blood flow. Thus, circulatory S1P confinement could be a primordial strategy of vertebrates in the development of a closed circulatory system. This review discusses the cellular and molecular basis of the S1P gradients and aims to interpret its physiological significance as a key feature of the closed circulatory system.
Topics: Animals; Cardiovascular System; Homeostasis; Humans; Lysophospholipids; Sphingosine
PubMed: 27813829
DOI: 10.1146/annurev-physiol-021014-071635 -
Advances in Biological Regulation Jan 2014Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, and the kinase that produces it have now emerged as key regulators of numerous cellular processes... (Review)
Review
Sphingosine-1-phosphate (S1P), a pleiotropic bioactive lipid mediator, and the kinase that produces it have now emerged as key regulators of numerous cellular processes involved in inflammation and cancer. Here, we review the importance of S1P in colitis and colitis-associated cancer (CAC) and discuss our recent work demonstrating that S1P produced by upregulation of SphK1 during colitis and associated cancer is essential for production of the multifunctional NF-κB-regulated cytokine IL-6, persistent activation of the transcription factor Stat3, and consequent upregulation of the S1P receptor, S1PR1. The effectiveness of the pro-drug FTY720 (known as fingolimod), approved for the treatment of multiple sclerosis, has become the gold standard for S1P-centric drugs, and will be used to illustrate the therapeutic value of modulating SphK1 and S1P receptor functions. We will discuss our recent results showing that FTY720/fingolimod administration interferes with the SphK1/S1P/S1PR1 axis and suppresses the NF-κB/IL-6/Stat3 malicious amplification loop and CAC. These preclinical studies suggest that FTY720/fingolimod may be useful in treating colon cancer in individuals with ulcerative colitis.
Topics: Animals; Chronic Disease; Humans; Intestinal Diseases; Lysophospholipids; Neoplasms; Signal Transduction; Sphingosine
PubMed: 24210073
DOI: 10.1016/j.jbior.2013.10.001