Sphingosine in apoptosis signaling (original) (raw)
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Sphingosine-dependent apoptosis: A unified concept based on multiple mechanisms operating in concert
Proceedings of The National Academy of Sciences, 2004
Exposure of 3T3͞A31 cells to serum-free medium, one type of apoptotic stimulus, causes a rapid increase in the sphingosine (Sph) level, which initiates a series of processes: (i) activation of caspase 3 through an enhanced ''cascade'' of caspases, (ii) release of the C-terminal-half kinase domain of PKC␦ (PKC␦ KD) by caspase 3, and (iii) activation of Sph-dependent kinase 1 (SDK1), which was previously identified as PKC␦ KD. The activation of caspase 3 and release of PKC␦ KD are inhibited strongly by the incubation of cells with the ceramidase inhibitor D-erythro-2-tetradecanoylamino-1phenyl-1-propanol and, to a much lesser extent, by L-cycloserine, an inhibitor of de novo ceramide synthesis. Exogenous addition of Sph or N,N-dimethyl-Sph to U937 cells causes caspase 3 activation and release of PKC␦ KD (SDK1), leading to apoptosis. The Sphinduced apoptotic process associated with activation of caspase 3 and release of PKC␦ KD (SDK1) may promote the proapoptotic effect of BAD or BAX through an increase of phosphorylated 14-3-3. In addition, Sph induces apoptosis through a separate process: the blocking of ''survival signal'' through the Akt kinase pathway induced by ␣31-mediated cell adhesion to laminin 10͞11 in extracellular matrix. We hereby propose a unified concept of Sph-dependent apoptosis based on these multiple mechanisms operating in concert.
Sphingosine kinase, sphingosine-1-phosphate, and apoptosis
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2002
The sphingolipid metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) play an important role in the regulation of cell proliferation, survival, and cell death. Cer and Sph usually inhibit proliferation and promote apoptosis, while the further metabolite S1P stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determines cell fate. The relevance of this ''sphingolipid rheostat'' and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that Sph kinase (SphK), the enzyme that phosphorylates Sph to form S1P, is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic Cer and Sph.
Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases
Biochimica et Biophysica Acta (BBA) - Biomembranes, 2006
Sphingolipids are ubiquitous components of cell membranes and their metabolites ceramide (Cer), sphingosine (Sph), and sphingosine-1phosphate (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.
Faseb Journal, 2008
Sphingosine-1-phosphate (S1P) is a bioactive lipid that regulates myriad important cellular processes, including growth, survival, cytoskeleton rearrangements, motility, and immunity. Here we report that treatment of Jurkat and U937 leukemia cells with the pan-sphingosine kinase (SphK) inhibitor N,N-dimethylsphingosine to block S1P formation surprisingly caused a large increase in expression of SphK1 concomitant with induction of apoptosis. Another SphK inhibitor, D,L-threo-dihydrosphingosine, also induced apoptosis and produced dramatic increases in SphK1 expression. However, up-regulation of SphK1 was not a specific effect of its inhibition but rather was a consequence of apoptotic stress. The chemotherapeutic drug doxorubicin, a potent inducer of apoptosis in these cells, also stimulated SphK1 expression and activity and promoted S1P secretion. The caspase inhibitor ZVAD reduced not only doxorubicin-induced lethality but also the increased expression of SphK1 and secretion of S1P. Apoptotic cells secrete chemotactic factors to attract phagocytic cells, and we found that S1P potently stimulated chemotaxis of monocytic THP-1 and U937 cells and primary monocytes and macrophages. Collectively, our data suggest that apoptotic cells may upregulate SphK1 to produce and secrete S1P that serves as a "come-and-get-me" signal for scavenger cells to engulf them in order to prevent necrosis.-Gude, Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a "come-and-getme" signal. FASEB J. 22, 2629 -2638 (2008)
The Journal of nutrition, 2003
The roles of extracellular regulated kinase (ERK) activation and mitogen-activated protein kinase phosphatase-1 (MKP-1) were examined in sphingosine-1-phosphate (S1P)-mediated inhibition of apoptosis in C3H10T 1/2 fibroblast cells. Apoptosis induced by the ceramide analog, C8-ceramine, was inhibited by S1P (ceramine/S1P). Stress activated protein kinase or c-Jun N-terminal kinase (SAPK/JNK) activation was significantly higher after ceramine and ceramine/S1P treatments. Ceramine/S1P treatment also significantly increased ERK activation and MKP-1 protein levels. ERK activation was required for the inhibition of apoptosis by S1P as shown using the mitogen-activated protein kinase kinase inhibitor, PD98059. Transfection with a dominant negative mutant construct of the MKP-1 gene prevented S1P inhibition of apoptosis and resulted in sustained SAPK/JNK activity. The MKP-1 mutant did not affect ERK activity, indicating that MKP-1 preferentially down-regulates SAPK/JNK in C3H10T 1/2 cells. ...
Advances in Biological Regulation, 2016
Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P 1-5. In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P 4) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis. Indeed, evidence will be presented here to demonstrate that S1P 4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient TALL lymphoblasts and TALL cell lines, we have demonstrated that SK2 inhibitors promote TALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth Introduction-Formation of the bioactive lipid, sphingosine 1-phosphate (S1P) is catalysed by sphingosine kinase. There are two isoforms of sphingosine kinase (SK1 and SK2) which differ in their subcellular localisations, regulation and functions (Pyne et al., 2009). The S1P formed by these enzymes can either be exported from cells (through transporter proteins e.g. Spns2) and act as a ligand on a family of five S1P-specific G protein coupled receptors (S1P 1-5) (Blaho and Hla, 2014) or can bind to specific intracellular target proteins. For instance S1P formed by nuclear SK2 inhibits HDAC1/2 activity to induce c-fos and p21 expression (Hait et al., 2009). Dephosphorylation of S1P is catalysed by S1P phosphatase and the sphingosine formed is then acylated to ceramide catalysed by ceramide synthase isoforms (Stiban et al., 2010). S1P can also be irreversibly cleaved by S1P lyase to produce (E)-2 hexadecenal and phosphoethanolamine (Degagné et al., 2014). The interconversion of ceramide to sphingosine and S1P has been termed the sphingolipid rheostat (Newton et al., 2015). In this model, shifting the balance toward ceramide induces apoptosis, while predominance of S1P formation promotes cell survival. For instance, ceramide activates protein phosphatase 2A (Dobrowsky et al., 1993), which dephosphorylates phosphorylated AKT (Zhou et al., 1998) and thereby alters BAD/Bcl2 regulation to induce apoptosis (Zundel and Giaccia, 1998). In contrast, S1P promotes cell survival, involving for instance, activation of the extracellular signal regulated kinase-1/2 (ERK-1/2) pathway (Pyne et al., 2009). However, the sphingolipid rheostat exhibits greater complexity, as certain ceramide species regulate processes other than apoptosis, such as autophagy and proliferation. This suggests temporal and spatial regulation, where the functionality of the sphingolipid rheostat is governed by compartmentalised signalling involving, for instance, ceramide synthase isoforms that produce different ceramide species with specific stress-dependent signalling functions that govern a defined cellular outcome e.g. apoptosis versus proliferation. The conversion of S1P to (E)-2 hexadecenal and phosphoethanolamine is also considered an exit point in the
A Review of the Role of Sphingolipids in Apoptosis Phenomenon
Journal of Babol University of Medical Sciences, 2018
BACKGROUND AND OBJECTIVE: Cancer is one of the major health problems in the world and chemotherapy is still the most common solution for its treatment. A great deal of studies in this area have been devoted to evaluating the occurrence of apoptosis as a key factor in preventing cell's escape from cell cycle regulation mechanisms. The aim of this study is to summarize the studies on metabolism, messenger pathways and effective pharmaceutical factors on sphingolipids involved in apoptosis. METHODS: In this review article, the national and international databases of PubMed, Scopus, Google Scholar, Web of Science, ISC and Magiran were searched for the keywords "apoptosis", "sphingolipids", "ceramide", "sphingosine" and "cancer" without time limit and the related material was collected. FINDINGS: Among the apoptotic messenger molecules, the key role of the sphingosine and ceramide has been considered as the cornerstone of sphingolipids in many of its controlling processes. It has been shown that ceramide is a key regulator in apoptosis, and increase in its cytoplasmic levels increase the proliferation of cascades resulting in programmed cell death. The bio-production and bio-destruction of ceramide is accomplished by the activity of several enzymes, and much evidence suggests the effect of external factors on enzyme systems. In contrast, the phosphorylated form of sphingosine is an important index for guiding cells toward proliferation and differentiation. It has been found that several commonly used chemotherapy drugs and compounds that are being studied in the treatment of cancer affect at least one of the enzymes of sphingolipids metabolism. CONCLUSION: Sphingolipids and the enzymes involved in their metabolism are introduced as new pharmacological targets for the induction of apoptosis, and it is obvious that analyzing the effective therapeutic factors and the ways of controlling them would be helpful in finding anticancer drugs.
Journal of Neurochemistry, 2001
Sphingosine-1-phosphate (SPP), a bioactive sphingolipid metabolite, suppresses apoptosis of many types of cells, including rat pheochromocytoma PC12 cells. Elucidating the molecular mechanism of action of SPP is complicated by many factors, including uptake and metabolism, as well as activation of specific G-protein-coupled SPP receptors, known as the endothelial differentiation gene-1 (EDG-1) family. In this study, we overexpressed type 1 sphingosine kinase (SPHK1), the enzyme that converts sphingosine to SPP, in order to examine more directly the role of intracellularly generated SPP in neuronal survival. Enforced expression of SPHK1 in PC12 cells resulted in significant increases in kinase activity, with corresponding increases in intracellular SPP levels and concomitant decreases in both sphingosine and ceramide, and marked suppression of apoptosis induced by trophic factor withdrawal or by C2-ceramide. NGF, which protects PC12 cells from serum withdrawal-induced apoptosis, also stimulated SPHK1 activity. Surprisingly, overexpression of SPHK1 had no effect on activation of two known NGF-stimulated survival pathways, extracellular signal regulated kinase ERK 1/2 and Akt. However, trophic withdrawal-induced activation of the stress activated protein kinase, c-Jun amino terminal kinase (SAPK/JNK), and activation of the executionary caspases 2, 3 and 7, were markedly suppressed. Moreover, this abrogation of caspase activation, which was prevented by the SPHK inhibitor N,N-dimethylsphingosine, was not affected by pertussis toxin treatment, indicating that the cytoprotective effect was likely not mediated by binding of SPP to cell surface Gi-coupled SPP receptors. In agreement, there was no detectable release of SPP into the culture medium, even after substantially increasing cellular SPP levels by NGF or sphingosine treatment. In contrast to PC12 cells, C6 astroglioma cells secreted SPP, suggesting that SPP might be one of a multitude of known neurotrophic factors produced and secreted by glial cells. Collectively, our results indicate that SPHK/SPP may play an important role in neuronal survival by regulating activation of SAPKs and caspases.