Sphingolipid metabolism affects the anticancer effect of cisplatin

Cisplatin, a DNA crosslinking agent, is widely used for the treatment of a variety of solid tumors. Numerous studies have demonstrated that sphingolipid metabolism, which acts as a target for cisplatin treatment, is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes. Ceramide (Cer), which is the central molecule of this network, has been established to induce apoptosis. However, another molecule, sphingosine-1-phosphate (S1P), exerts the opposite function, i.e., serves as a regulator of pro-survival. Other sphingolipid molecules, including dihydroceramide, ceramide-1-phosphate, glucosylceramide (GluCer), and sphingosine (Sph), or sphingolipid catalytic enzymes such as Sph kinase (SphK), Cer synthase (CerS), and S1P lyase, have also attracted considerable attention, particularly Cer, GluCer, SphK, CerS, and S1P lyase, which have been implicated in cisplatin resistance. This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin, particularly in relation to induction of apoptosis and drug resistance.     

Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer

Beside their structural role for the cell membrane the family of sphingolipids act as effector molecules in signal transduction with links to various aspects of cancer initiation, progression and treatment response. The “sphingolipid rheostat” balances between apoptosis inducing ceramid and growth promoting sphingosine-1-phosphate. We analyzed gene expression of 43 proteins from this pathway in different subtypes of breast cancer using microarray data of 1,269 tumor samples (test set n = 171; validation sets n = 1098) and observed significant differences for several genes. Sphingosine kinase 1 (SPHK1), ceramide galactosyltransferase (UGT8), and Ganglioside GD3-Synthase (ST8SIA1) displayed higher expression among ER negative tumors. In contrast, glucosylceramidsynthase (GCS), dihydroceramidsynthases (LASS4, LASS 6) and acid ceramidase (ASAH1) were higher expressed in ER positive samples. Survival analysis revealed a worse outcome of patients with high SPHK1 expression. To avoid a confounding effect of the ER status we also restricted the analysis to 750 patients with ER positive tumors. Again a worse outcome was observed for tumors displaying high SPHK1 expression. While 75.8 ± 1.9% of the patients with tumors low in SPHK1 expression were free of metastasis at 5 years, this was the case for only 64.9 ± 3.6% of patients with tumors displaying high SPHK1 expression (P = 0.008). Immunohistochemistry identified the carcinoma cells as the major source of SPHK1 expression in the tumor. The correlation of SPHK1 with a poor prognosis as well as its high expression among ER negative tumors are in line with the antiapoptotic and proliferative properties of its product sphingosine-1-phosphate. Targeting of the sphingolipid rheostat may thus open new treatment options.     

Sphingolipid activator protein deficiency in a 16-week-old atypical Gaucher disease patient and his fetal sibling: Biochemical signs of combined sphingolipidoses

We describe a patient who presented shortly after birth with hyperkinetic behaviour, myoclonia, respiratory insufficiency and hepatosplenomegaly. Gaucher-like storage cells were found in bone marrow. A liver biopsy showed massive lysosomal storage morphologically different to that in known lipid storage disorders. Biochemically, the patient had partial deficiencies of -galactocerebrosidase, -glucocerebrosidase and ceramidase in skin fibroblast extracts, but the sphingomyelinase activity was normal. Glucosyl ceramide and ceramide were elevated in liver tissue. Loading of cultured fibroblasts with radioactive sphingolipid precursors indicated a profound defect in ceramide catabolism. Immunological studies in fibroblasts showed a total absence of cross-reacting material to sphingolipid activator protein 2 (SAP-2). The patient died at 16 weeks of age. The fetus from his mother's next pregnancy was similarly affected. The possibility that the disorder results from a primary defect at the level of SAP-2 is discussed. We have named this unique disorder SAP deficiency.     

Cutaneous lipid synthesis during late fetal development in the rat

Lipid synthesis in fetal skin may be important both for the development of a mature epidermal permeability barrier and for growth. In these studies, we measured cutaneous cholesterol, sphingolipid and fatty acid synthesis during the critical period of epidermal barrier development in fetal rats to determine whether barrier function influences synthetic rates. In addition, the activities of HMG CoA reductase, serine palmitoyl transferase and acetyl coenzyme A carboxylase were evaluated. In whole skin, synthesis of cholesterol, ceramide, sphingomyelin and fatty acid decreased from day 17 to day 21 of gestation, as did the activity of HMG CoA reductase, serine palmitoyl transferase and acetyl coenzyme A carboxylase. In both the epidermis and dermis, a decrease in cholesterol, ceramide, sphingomyelin and fatty acid synthesis was measured over days 19–21 of gestation. Epidermal HMG CoA reductase activity also decreased over this same time period. In summary, epidermal and dermal synthetic rates and enzyme activity were highest early in gestation when the barrier was least competent and decreased as competence was achieved. Since other studies with mature animals have revealed that epidermal synthetic rates and enzyme activity are highest when barrier disruption is maximal, enhanced epidermal lipid synthesis precedes the estabilishment of a competent barrier in both fetal and mature rodents.     

A concise synthesis of a promising protein kinase C inhibitor: D-erythro-sphingosine

In this study, we explored a convenient and concise route for synthesis of D-erythro-sphingosine 1 from commercially available and cheap L-serine. The key steps are simple preparation of amino ketone 5 from Weinreb amide 3 and high diastereoselective reduction of amino ketone 5 to give the natural erythro-(anti-) isomer.     

Plasma metabolites mediate the association of coarse grain intake with blood pressure in hypertension-free adults

Background and aimsIncreased intake of whole/coarse grains was associated with improved blood pressure control, but concurrent metabolism alterations are less clear. We sought to identify metabolomic profiles of blood pressure, and to explore their mediation effects on the coarse grain intake-blood pressure association among young adults free of hypertension.Methods and resultsPlasma metabolome of 86 participants from the Carbohydrate Alternatives and Metabolic Phenotypes study was characterized by untargeted lipidomics and metabolomics using liquid chromatography–high-resolution mass spectrometry. We identified 24 and 117 metabolites associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively, using random forest modeling and partial correlation analysis. Moreover, metabolite panels for highly specific prediction of blood pressure (8 metabolites for SBP and 11 metabolites for DBP) were determined using ten-fold cross-validated ridge regression (R² ≥ 0.70). We also observed an inverse association between metabolite panel of SBP (β ± SE = −0.02 ± 0.01, P = 0.04) or DBP (β ± SE = −0.03 ± 0.01, P = 0.02) and coarse grain intake. Furthermore, we observed significant mediating effects of metabolites, in particular, sphingolipid ceramides, on the association between coarse grain exposure and blood pressure using both bias-corrected bootstrap tests and high-dimensional mediation analysis adapted for large-scale and high-throughput omics data.ConclusionsWe identified metabolomic profiles specifically associated with blood pressure in young Chinese adults without diagnosed hypertension. The inverse association between coarse grain intake and blood pressure may be mediated by sphingolipid metabolites.     

Localization of epidermal sphingolipid synthesis and serine palmitoyl transferase activity: alterations imposed by permeability barrier requirements

Sphingolipids, the predominant lipid species in mammalian stratum corneum play, a central role in permeability barrier homeostatis. Prior studies have shown that the epidermis synthesizes abundant sphingolipids, a process regulated by barrier requirements, and that inhibition of sphingolipid synthesis interferes with barrier homeostasis. To investigate further the relationship between epidermal sphingolipid metabolism and barrier function, we localized sphingolipid synthetic activity in murine epidermis under basal conditions, and following acute (acetone treatment) or chronic (essential fatty acid deficiency, EFAD) barrier perturbation, using dithiothreitol and/or the staphylococcal epidermolytic toxin to isolate the lower from the outer epidermis. Under basal conditions, both the activity of serine palmitoyl transferase (SPT), the rate-limiting enzyme of sphingolipid synthesis, and the rates of³H-H₂O incorporation into sphingolipids were nearly equivalent in the lower and the outer epidermis. Following acute barrier perturbation, SPT activity increased significantly in both the lower (35%;P < 0.05) and the outer epidermal layers (60%;P < 0.01). The rates of³H-H₂O incorporation into each major sphingolipid family, including ceramides, glucosylceramides and sphingomyelin, increased significantly in both the lower and the outer epidermis of treated flanks after acute barrier disruption. Finally, SPT activity was modestly elevated (20%;P < 0.01) in the lower but not in the outer epidermis of EFAD animals. These studies demonstrate the ability of both lower and outer epidermal cells to generate sphingolipids, and that permeability barrier homeostatic mechanisms appear to differentially regulate SPT acitivity and sphingolipid synthesis in the lower and the outer epidermis in response to acute and chronic barrier perturbation. Moreover, intraepidermal sites of sphingolipid synthesis displayed distinctive differences in the localization and alterations of cholesterologenesis in response to equivalent barrier perturbations.     

神经鞘脂代谢与铁死亡在肝癌中的研究进展

铁死亡（ferroptosis）是不同于凋亡的一种细胞死亡方式,最新研究发现在肝癌治疗以及肝癌耐药等过程铁死亡参与其中。大量研究证实神经鞘脂代谢和肝癌发生、发展密切相关。神经鞘脂代谢通路和铁死亡通路存在交互作用,两者都与肝癌密切相关。本文就神经鞘脂代谢通路与铁死亡通路的交互作用以及对肝癌发生、发展、治疗等方面影响的近期研究进展进行阐述。     

Growth Inhibitory and Pro-Apoptotic Effects of Hirsuteine in Chronic Myeloid Leukemia Cells through Targeting Sphingosine Kinase 1

Chronic myeloid leukemia (CML) is a slowly progressing hematopoietic cell disorder. Sphingosine kinase 1 (SPHK1) plays established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers, including leukemia. However, small-molecule inhibitors targeting SPHK1 in CML still need to be developed. This study revealed the role of SPHK1 in CML and investigated the potential anti-leukemic activity of hirsuteine (HST), an indole alkaloid obtained from the oriental plant Uncaria rhynchophylla, in CML cells. These results suggest that SPHK1 is highly expressed in CML cells and that overexpression of SPHK1 represents poor clinical outcomes in CML patients. HST exposure led to G2/M phase arrest, cellular apoptosis, and downregulation of Cyclin B1 and CDC2 and cleavage of Caspase 3 and PARP in CML cells. HST shifted sphingolipid rheostat from sphingosine 1-phosphate (S1P) towards the ceramide coupled with a marked inhibition of SPHK1. Mechanistically, HST significantly blocked SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways. In addition, HST can be docked with residues of SPHK1 and shifts the SPHK1 melting curve, indicating the potential protein-ligand interactions between SPHK1 and HST in both CML cells. SPHK1 overexpression impaired apoptosis and proliferation of CML cells induced by HST alone. These results suggest that HST, which may serve as a novel and specific SPHK1 inhibitor, exerts anti-leukemic activity by inhibiting the SPHK1/S1P/S1PR1 and BCR-ABL/PI3K/Akt pathways in CML cells, thus conferring HST as a promising anti-leukemic drug for CML therapy in the future.     

Synthesis and cytotoxicity of new aromatic ceramide analogs with alkylsulfonamido chains

A series of D-erythro ceramide analogues, N-(2S, 3R, 4E)-1, 3-dihydroxy-5-phenyl pent-4-en-2-yl alkyl sulfonamides, were synthesized and evaluated for their in vitro cytotoxic activities against five human tumor cell lines. The aromatic sulfon amido ceramide analogue (10f) showed more potent cytotoxic activity than that of the B13, indicating that a sulfonamide group appears to serve as a bioisostere of an amide in drug design. Variations in the alkyl sulfonyl chain length significantly influenced the cytotoxic activity of the sulfonamido ceramide analogues, but the introduction of a para halogen on the phenyl ring of aromatic ceramide analogues had no affect on the activity.