sphingosine-kinase and ceramide-1-phosphate

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.

Topics: Animals; Cell Movement; Ceramides; Humans; Inflammation; Lysophospholipids; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingolipids; Sphingosine

The development and progression of colorectal cancer (CRC), a major cause of cancer-related death in the western world, is accompanied with alterations of sphingolipid (SL) composition in colon tumors. A number of enzymes involved in the SL metabolism have been found to be deregulated in human colon tumors, in experimental rodent studies, and in human colon cancer cells in vitro. Therefore, the enzymatic pathways that modulate SL levels have received a significant attention, due to their possible contribution to CRC development, or as potential therapeutic targets. Many of these enzymes are associated with an increased sphingosine-1-phosphate/ceramide ratio, which is in turn linked with increased colon cancer cell survival, proliferation and cancer progression. Nevertheless, more attention should also be paid to the more complex SLs, including specific glycosphingolipids, such as lactosylceramides, which can be also deregulated during CRC development. In this review, we focus on the potential roles of individual SLs/SL metabolism enzymes in colon cancer, as well as on the pros and cons of employing the current in vitro models of colon cancer cells for lipidomic studies investigating the SL metabolism in CRC.

Topics: Acid Ceramidase; Alkaline Ceramidase; Animals; Ceramides; Colonic Neoplasms; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Lactosylceramides; Lipid Metabolism; Lysophospholipids; Neutral Ceramidase; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins c-akt; Sphingolipids; Sphingosine; Sphingosine N-Acyltransferase; Tumor Cells, Cultured

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.

Topics: Animals; Biomarkers, Tumor; Ceramides; Humans; Inflammation; Inflammation Mediators; Lysophospholipids; Models, Biological; Neoplasms; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine

Simple bioactive sphingolipids include ceramide, sphingosine and their phosphorylated forms sphingosine 1-phosphate and ceramide 1-phosphate. These molecules are crucial regulators of cell functions. In particular, they play important roles in the regulation of angiogenesis, apoptosis, cell proliferation, differentiation, migration, and inflammation. Decoding the mechanisms by which these cellular functions are regulated requires detailed understanding of the signaling pathways that are implicated in these processes. Most importantly, the development of inhibitors of the enzymes involved in their metabolism may be crucial for establishing new therapeutic strategies for treatment of disease.

Topics: Animals; Ceramidases; Ceramides; Disease; Humans; Inflammation; Isoenzymes; Lysophospholipids; Macrophages; Molecular Structure; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingolipids; Sphingosine

During the last several years, sphingolipids have been identified as a source of important signaling molecules. Particularly, the understanding of the distinct biological roles of ceramide, sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P) and lyso-sphingomyelin in the regulation of cell growth, death, senescence, adhesion, migration, inflammation, angiogenesis and intracellular trafficking has rapidly expanded. Additional studies have elucidated the biological roles of sphingolipids in maintaining a homeostatic environment in cells, as well as in regulating numerous cellular responses to environmental stimuli. This review focuses on the role of S1P and C1P in maintaining Ca2+ homeostasis. By studying changes in the metabolism of S1P and C1P in pathological conditions, it is hoped that altered sphingolipid-metabolizing enzymes and their metabolites can be used as therapeutic targets.

Topics: Animals; Calcium; Calcium Channels; Calcium Signaling; Ceramides; Homeostasis; Humans; Lysophospholipids; Neovascularization, Physiologic; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

Acute lymphoblastic leukemia (ALL) is the most common fatal cancer in people younger than 20 years of age. This study was designed to explore the anti-leukemia activity of physcion 8-O-β-glucopyranoside (PG) in B-cell ALL.. NALM6 and SupB15 cells were used as model cell lines. Cell viability, cell apoptosis, cell cycle distribution were determined by CCK-8 assay, DNA fragmentation assay and flow cytometry, and flow cytometry, respectively. Expression of proteins involved in cell apoptosis and cell cycle regulation was determined by western blot and the levels of ceramide and sphingosine 1-phosphate (S1P) were determined by ELISA. Activity of sphingosine kinase 1 (SphK1) was also determined with a Sphingosine Kinase Assay Kit. In the present study, both model cell lines were transfected with siRNA targeting SphK1 or an overexpression plasmid to examine the role of SphK1 in the anti-leukemia activity of PG. Moreover, the efficacy of PG was examined in vivo in a mouse model by measuring survival and spleen weight.. Our results provided experimental evidence that PG could significantly induce apoptosis and cell cycle arrest in vitro. Mechanistically, the anti-leukemia activity of PG was mediated by its ability to repress SphK1 and thus modulate ceramide-S1P rheostat. Moreover, the anti-leukemia activity of PG was also verified in a murine model.. Collectively, our results indicate that PG may be a promising agent for the treatment of B-cell leukemia.

Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Ceramides; DNA Damage; Emodin; Glucosides; Humans; Lysophospholipids; Mice; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); RNA, Small Interfering; Sphingosine

Topics: Ceramides; Detergents; Diacylglycerol Kinase; Enzyme Stability; Organophosphates; Phosphotransferases (Alcohol Group Acceptor); Potassium Chloride; Reducing Agents; Signal Transduction