Resistance to alkyl-lysophospholipid-induced apoptosis due to downregulated sphingomyelin synthase 1 expression with consequent sphingomyelin- and cholesterol-deficiency in lipid rafts

Luit, Arnold H. van der; Budde, Marianne; Zerp, S.F.; Caan, W.; Klarenbeek, Jeffrey; Verheij, Marcel; Blitterswijk, Wim J. van

doi:10.1042/bj20061178

Cited by 80 publications

(78 citation statements)

References 43 publications

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“…33 Similar findings were reported in S49, a murine lymphoma cell line. 27 Considering the ability of FasL Sphingomyelin synthase 1 in FasL-induced apoptosis E Lafont et al to trigger a caspase-dependent inhibition of SMS activity in Jurkat cells, we hypothesized that SMS1 is a putative target of caspases.…”

Section: Resultsmentioning

confidence: 99%

“…Murine lymphoma cells, completely deficient for SMS activity and lacking SM, were resistant toward alkyllysophosphatidylcholine. 27 Fas-mediated apoptosis was partly impaired in a murine leukemia cell line deficient in SMS, and overexpression of SMS1 restored full caspase activation and cell death. 28 Thus, a complete and sustained inhibition of SMS might alter membrane composition and properties through SM depletion and confer partial cell death resistance.…”

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confidence: 99%

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Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL-triggered cell death

et al. 2009

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Ceramide can be converted into sphingomyelin by sphingomyelin synthases (SMS) 1 and 2. In this study, we show that in human leukemia Jurkat cells, which express mainly SMS1, Fas ligand (FasL) treatment inhibited SMS activity in a dose-and timedependent manner before nuclear fragmentation. The SMS inhibition elicited by FasL (1) was abrogated by benzyloxycarbonyl valyl-alanyl-aspartyl-(O-methyl)-fluoromethylketone (zVAD-fmk), a broad-spectrum caspase inhibitor; (2) did not occur in caspase-8-deficient cells and (3) was not affected in caspase-9-deficient cells. Western blot experiments showed SMS1 cleavage in a caspase-dependent manner upon FasL treatment. In a cell-free system, caspase-2, -7, -8 and -9, but not caspase-3 and -10, cleaved SMS1. In HeLa cells, SMS1 was Golgi localized and relocated throughout the cytoplasm in cells exhibiting an early apoptotic phenotype on FasL treatment. zVAD-fmk prevented FasL-induced SMS1 relocation. Thus, FasL-mediated SMS1 inhibition and relocation depend on caspase activation and likely represent proximal events in Fas signaling. FasL-induced ceramide production and cell death were enhanced in cells stably expressing an siRNA against SMS1. Conversely, in cells stably overexpressing SMS1, FasL neither increased ceramide generation nor efficiently induced cell death. Altogether, our data show that SMS1 is a novel caspase target that is functionally involved in the regulation of FasL-induced apoptosis.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL-triggered cell death

et al. 2009

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“…Regarding the role of SMS in cell death, some studies reported that downregulation of SMS1 confers resistance to stress-induced apoptosis [40,41].…”

Section: Page 17 Of 43mentioning

confidence: 99%

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

Salma

Lafont

Therville

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 AbstractMarine environment has frequently afforded a variety of biologically active compounds with strong anticancer and cytotoxic properties. In the present study, the mechanism of action of Jaspine B, an anhydrophytosphingosine derivative isolated from the marine sponge Jaspis sp., was investigated. Jaspine B was able to doseand time-dependently decrease the viability of murine B16 and human SK-Mel28 melanoma cells. On these cells, Jaspine B treatment triggered cell death by typical apoptosis as illustrated by phosphatidylserine externalization, the release of cytochrome c and caspase processing. These effects were associated with increased intracellular ceramide levels owing to perturbed ceramide metabolism. Indeed, Jaspine B exposure strongly inhibited the activity of sphingomyelin synthase (SMS), an enzyme that converts de novo ceramide into the membrane lipid sphingomyelin.Moreover, whereas Jaspine B-induced cell death was enhanced in SMS1-depleted cells, it was strongly inhibited in cells that stably overexpress human SMS1. Finally, the cytotoxic effects of Jaspine B truncated analogs were also shown to be dependent on SMS activity.Altogether, Jaspine B is able to kill melanoma cells by acting on SMS activity and consequently on ceramide formation, and may represent a new class of cytotoxic compounds with potential applications in anticancer melanoma therapy.

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“…Interestingly, expression of both SMS1 and SMS2 has been observed in all adherent cell lines analyzed so far (breast cancer MCF-7 cells, cervical cancer HeLa cells, hepatocellular carcinoma HepG2 cells, colon cancer CaCo 2 cells, human lung fibroblasts, human epithelial HEK-293 cells, mouse melanoma MEB4, mouse fibroblasts) whereas expression of SMS2 seems to be very low or absent in the majority of suspension cell lines (S49, WR19L/Fas, Ramos and U937 lymphoma cells, HL-60, Molt-4 and K562 leukemia cells and primary human B, T and monocytic cells) 58,62,[72][73][74] and Luberto, unpublished observations). Since SMS2 is in part localized at the plasma membrane, with its catalytic site oriented toward the outside of the cell and it is expressed mainly in adherent cells, it may serve a specialized function in cell-cell or cell to matrix interactions.…”

Section: Differential Expression Of Sms1 and Sms2mentioning

confidence: 99%

“…Subsequently, the involvement of SMS1 in the maintenance of raft homeostasis has been postulated in S49 mouse lymphoma cells. 73 A variant S49 cell line resistant to apoptosis induced by alkyl-lysophospholipids (ALP) turned out to be deficient in SM synthesis due to down-regulation of SMS1 expression. Since ALP appears to be internalized via raft-dependent endocytosis, it was suggested that SM depletion perturbs the internalization of ALP in the resistant S49 variant.…”

Section: Sms1 and Sms2 As Regulators Of Sm Homeostasis And Receptor-mmentioning

confidence: 99%

Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

Holthuis

Luberto

2010

Advances in Experimental Medicine and Biology

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In the last five years tremendous progress has been made toward the understanding of the mechanisms that govern sphingomyelin (SM) synthesis in animal cells. In line with the complexity of most biological processes, also in the case of SM biosynthesis, the more we learn the more enigmatic and finely tuned the system appears. Therefore with this review we aim first, at highlighting the most significant discoveries that advanced our knowledge and understanding of SM biosynthesis, starting from the discovery of SM to the identification of the enzymes responsible for its production; and second, at discussing old and new riddles that such discoveries pose to current investigators.

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Resistance to alkyl-lysophospholipid-induced apoptosis due to downregulated sphingomyelin synthase 1 expression with consequent sphingomyelin- and cholesterol-deficiency in lipid rafts

Cited by 80 publications

References 43 publications

Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL-triggered cell death

Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL-triggered cell death

The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism

Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

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