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Review Article the Role of Sphingosine-1-Phosphate and Ceramide-1- Phosphate in Inflammation and Cancer

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Review Article the Role of Sphingosine-1-Phosphate and Ceramide-1- Phosphate in Inflammation and Cancer Hindawi Mediators of Inflammation Volume 2017, Article ID 4806541, 17 pages https://doi.org/10.1155/2017/4806541 Review Article The Role of Sphingosine-1-Phosphate and Ceramide-1- Phosphate in Inflammation and Cancer Nitai C. Hait and Aparna Maiti Division of Breast Surgery, Departments of Surgical Oncology and Molecular & Cellular Biology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA Correspondence should be addressed to Nitai C. Hait; [email protected] Received 31 May 2017; Revised 1 August 2017; Accepted 30 August 2017; Published 15 November 2017 Academic Editor: Alice Alessenko Copyright © 2017 Nitai C. Hait and Aparna Maiti. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1. Introduction recruited to the inflamed tissue from the circulation where they are involved in assisting resolution of inflammation. Sphingolipids and their derivatives are important structural These processes are marked by the synthesis and secretion components of mammalian cell membranes. Sphingolipid of cytokines, chemokines, extracellular matrix proteins, metabolites, particularly ceramide, sphingosine-1-phosphate and various lipid mediators including sphingolipid (S1P), and ceramide-1-phosphate (C1P), are lipid mediators metabolites. Ceramides are the central sphingolipid metab- that regulate varieties of cellular functions which include cell olite known to be part of proapoptotic signaling as well as growth, survival, migration, immune cell trafficking, angio- inflammatory signaling [10–12]. It has been suggested that genesis, inflammation, and cancer [1–3]. It is well established orosomucoid (ORM) (yeast-) like protein isoform 3 that S1P and C1P are the regulators of sphingolipid rheostat (ORMDL3) gene may be linked with susceptibility to where they reduce proapoptotic ceramide and enhance asthma, a chronic airway inflammation and hyperactivity prosurvival signaling [4, 5]. Inflammation forms the basis condition [13, 14]. ORMDL3 yeast ortholog is a negative of many physiological and pathological processes [6, 7]. regulator of de novo ceramide biosynthesis [15]. However, Chronic inflammation is associated with asthma, chronic we found that high expression of ORMDL3 in lung epithe- obstructive pulmonary disease (COPD), obesity, type II lial cells and macrophages enhances ceramide production, diabetes, autoimmune disorders, inflammatory bowel disease, which promoted chronic inflammation, airway hyper and cancer [8, 9]. In response to local tissue damage or infec- responsiveness, and mucus production during house dust tion, neutrophils, macrophages, and other immune cells are mite-induced allergic asthma in a mouse model [16]. 2 Mediators of Inflammation OH Serine + palmitoyl CoA HOCH2 NH2 Sphingosine SPT O OH - 3-Ketosphinganine O-P-O-CH2 - O NH S1P - 2 Reductase De novo OH Sphinganine pathway HOCH2 NH Dh-CerS GCS GluCer Complex SLs O Cer Dihydroceramide O OH - Des O-P-O-CH2 GCase - -O NH SMS CerS SM Cer Sph Salvage pathway O C1P SMase CDase CERK CPPase SphK1 SPPase SphK2 C1P S1P SPL Ethanolamine phosphate + hexadecenal Glycerolipids (a) (b) Figure 1: Biosynthesis of ceramide, sphingosine-1-phosphate, and ceramide-1-phosphate (a). Chemical structures of sphingolipids (b). Ceramide is the central sphingolipid molecule of sphingolipid metabolic pathways. Three major pathways are responsible to produce ceramide. Ceramide is produced by de novo pathway in the ER with a series of enzymatic reactions. Ceramide is produce from SM by SMase action. The salvage pathway generates ceramide from sphingosine that generates from the metabolism of complex sphingolipids. Ceramide is now can be converted to C1P by CERK enzyme. Ceramide can be converted to sphingosine by ceramidase. Sphingosine is now phosphorylated by sphingosine kinases to form S1P. S1P can be converted back to sphingosine by SPPase or can be irreversibly broken down by sphingosine phosphate lyase (SPL) to ethanolamine phosphate and 2-trans hexadecenal for phosphatidylethanolamine and glycerolipids, respectively. Further, nasal administration of the drug FTY720, an 2. Sphingolipid Metabolism immunosuppressant agent, reduced ceramide levels by lowering ORMDL3 expression [16, 17]. In addition, it The de novo synthesis of sphingolipids in the endoplasmic was found that ORMDL3 also regulates ceramides during reticulum (ER) starts with the action of serine palmitoyl- IL-1β-induced sterile inflammation [17]. Ceramide is transferase (SPT) that forms 3-ketosphinganine from serine enhanced in response to lipopolysaccharide (LPS), saturated and palmitoyl coenzyme A (CoA). It has been suggested that fatty acids, or TNFα. Ceramide promotes inflammation by SPT activity is negatively regulated by ORMDL proteins [15], varieties of pathways leading to an enhanced effect of obesity which has been identified as a potential risk factor for child- [12]. Ceramide stimulates the action of protein phosphatase hood asthma [14, 16]. 3-Ketosphinganine is converted to 2 (PP2), which dephosphorylates AKT [18], decreases sphinganine by a reductase. Ceramide synthase catalyzes survival, and activates Nlrp3 inflammasome to generate the incorporation of an acyl group from fatty acyl-CoA to active proinflammatory IL-1β [19, 20]. Initially, it was form dihydroceramide. A desaturase converts dihydrocera- experimentally shown that ceramide stimulates Ca2+-depen- mide to ceramide by introducing a double bond in positions dent cytosolic phospholipase A2 (cPLA2) and generates 4-5 trans (Figure 1). Ceramide is the central sphingolipid of cyclooxygenase 2- (Cox2-) mediated prostaglandins in the sphingolipid metabolism. Ceramide is further converted response to TNFα [21]. However, it has been shown that to sphingomyelin by sphingomyelin synthase, to glucosylcer- ceramide-1-phosphate (C1P), produced by the ceramide amide by glucosylceramide synthase to form complex sphin- kinase (CERK), activates and translocates cPLA2 more golipids, to sphingosine by ceramidase, or to C1P by CERK. potently than ceramide to generate prostaglandins and Sphingosine is further converted to S1P by SphKs. S1P can inflammatory signaling [22]. Growing evidence and few be converted back to sphingosine by the S1P phosphatase, recent reviews also suggested that sphingosine-1-phosphate or it can be irreversibly degraded by S1P lyase to ethanol- (S1P), produced by sphingosine kinases (SphKs), is a amine phosphate and hexadecanal (palmitaldehyde). Metab- progrowth and proinflammatory lipid mediator for cancer olism of ceramide to complex sphingolipids occurs in the progression [10, 23–25]. However, recent data also suggested Golgi bodies. Ceramide is delivered to Golgi by ceramide that both S1P and C1P might have anti-inflammatory transport protein (CERT) [26]. C1P is formed in the Golgi roles in certain settings. This review focuses on the current by CERK [27]. Once the C1P is formed, it is delivered to understanding of the role of S1P and C1P in inflammation the plasma membrane for various physiological signaling and cancer. processes by the C1P transfer protein (CPTP) [28] or CPTP Mediators of Inflammation 3 Signals Autocrine signaling S1P Paracrine signaling SMase CDase SphK1 SM Cer Sph S1P Plasma membrane Lysosome Endocytosis CPTP Other organelles? aSMase SM Intracellular GSL signaling Cer Cer GCase C1P S1P CERK aCDase Mitochondrion Sph SphK1 SM Salvage pathway nSMase Sph Cer Golgi Serine + CERT CDase palmitoyl CoA Sph De novo Cer SphK2 pathway S1P Transcription Respiration ER of genes and ETC nSMase1 CERK? SM Cer C1P CDase Sph Nucleus signaling SphK2 Nuclear epigenetic S1P] Figure 2: Cellular localization of sphingosine-1-phosphate and ceramide-1-phosphate. ER is the source of ceramide synthesis. Ceramide translocates to the Golgi by ceramide transport protein (CERT) for the synthesis of C1P by Golgi-localized CERK. Ceramide phosphate transfer protein (CPTP) was hypothesized to deliver C1P to the other organelles. Ceramide is produced
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