Ceramide metabolite, not intact ceramide molecule, may be responsible for cellular toxicity

Tserng, Kou‐Yi; Griffin, Ronda

doi:10.1042/bj20031733

Cited by 37 publications

(20 citation statements)

References 31 publications

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“…agreement with a recent report (22), the presence of dodecane did not enhance the uptake and metabolism of fluorescent NBD-Cer, which was followed in parallel (Fig. 5).…”

Section: Discussionsupporting

confidence: 80%

Effects of ceramide-1-phosphate on cultured cells: dependence on dodecane in the vehicle

Tauzin

Gräf

Sun

et al. 2007

Journal of Lipid Research

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Ceramide-1-phosphate (C1P), the product of ceramide kinase, is a sphingophospholipid with recently recognized signaling properties. In particular, it was reported to be mitogenic and capable of direct stimulation of cytosolic phospholipase A 2a . Much of the present knowledge has relied on the use of C1P of various acyl chain lengths, together with diverse protocols to deliver it to cultured cells. A mixture of ethanol (or methanol) with dodecane, as the vehicle, has become popular. However, the contribution of this solvent to the observed effects of C1P has not been documented. Here, we show that addition of C1P in ethanoldodecane to culture medium leads to irreversible cytotoxic effects. These culminate in mitochondrial swelling, vacuole formation, and cell death. Not only the toxicity of C1P, but also its ability to trigger prostaglandin E 2 release, is fully dependent upon addition of a premade C1P-dodecane mixture. Furthermore, we show that these effects are not restricted to C1P. They result from the capacity of dodecane to interact with phospholipids; hence, they go undetected with a vehicle control. This study should raise awareness about the use of dodecane for phospholipid delivery and, in turn, help in unraveling C1P signaling, which is still poorly

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“…agreement with a recent report (22), the presence of dodecane did not enhance the uptake and metabolism of fluorescent NBD-Cer, which was followed in parallel (Fig. 5).…”

Section: Discussionsupporting

confidence: 80%

Effects of ceramide-1-phosphate on cultured cells: dependence on dodecane in the vehicle

Tauzin

Gräf

Sun

et al. 2007

Journal of Lipid Research

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“…Few studies have reported the status of dihydroceramide during apoptosis. Interestingly, Tserng and Griffin (40) recently reported the same pattern of dihydroceramide, but not ceramide, accumulation along with cell death when HL-60 human leukemia cells were treated with natural ceramide or N-oleoylethanolamide, a ceramidase inhibitor, as well as its inactive homologue, Npalmitoylethanolamide (40). Our current data, together with those gathered by Tserng and Griffin, therefore, indicate that this pattern of dihydroceramide and dihydrosphingosine accumulation is independent of the cell types and the reagents applied and therefore may represent a previously unrecognized type of cellular response to stress.…”

Section: Discussionmentioning

confidence: 99%

γ-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis

Jiang

Wong

Fyrst

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

184

147

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␥-Tocopherol (␥T), the predominant form of vitamin E in diets, but not ␣-tocopherol, the major vitamin E form in tissues and supplements, inhibits proliferation of prostate cancer cells (LNCaP and PC-3) and lung cancer cells (A549). In contrast, at similar concentrations, ␥T has no effect on normal prostate epithelial cells. Combinations of some vitamin E forms, such as ␥T and ␦-tocopherol, exhibit additive or synergistic inhibitory effects. In this study, ␥T or its combination with ␦-tocopherol induced apoptosis in androgen-sensitive prostate LNCaP, but not in androgenresistant PC-3 cells, by the induction of cytochrome c release, activation of caspase 9 and caspase 3, cleavage of poly-ADP-ribose polymerase (PARP), and involvement of caspase-independent pathways. Myriocin and fumonisin B1, specific inhibitors of key enzymes (serine palmitoyltransferase and dihydroceramide synthase, respectively) in de novo synthesis of sphingolipids, significantly protected cells from ␥T-induced DNA fragmentation, cytochrome c release, PARP cleavage, and the formation of active caspase 3. Compared with vehicle-treated controls, ␥T treatment led to pronounced dihydroceramide and dihydrosphingosine accumulation, which preceded morphological and biochemical manifestations of apoptosis. In contrast, ceramide and shpingosine levels did not increase until day 3, when substantial cell death took place. Our study demonstrates that ␥T and mixed vitamin E forms induce cell death by interrupting the de novo sphingolipid pathway in a prostate cancer cell line. Thus, certain vitamin E forms may be valuable as anticancer agents.

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“…Additionally, Jiang et al (39) could also demonstrate for the chemotherapeutic g-tocopherole, which blocks the DEGS, that an accumulation of endogenously produced C 16:0 -dhCer induces apoptosis in lung cancer cells (A549). Moreover, Tserng and Griffin (40) elucidated that natural C 16:0 -Cer exogenously added to human leukemia cells induces apoptosis via accumulation of dhCers. Deregulation of dhCer and Cer levels in fibroblasts, caused by the loss of the CLN9 gene, has dramatic consequences for cell growth, inasmuch as these cells show rapid growth on the one hand but increased apoptosis on the other hand (41).…”

Section: Discussionmentioning

confidence: 99%

The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis

Schiffmann

Sandner

Schmidt

et al. 2009

Journal of Lipid Research

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Sphingolipids such as ceramides (Cers) play important roles in cell proliferation, apoptosis, and cell cycle regulation. An increased Cer level is linked to the cytotoxic effects of several chemotherapeutics. Various selective cyclooxygenase-2 (COX-2) inhibitors induce anti-proliferative effects in tumor cells. We addressed the possible interaction of the selective COX-2 inhibitors, coxibs, with the sphingolipid pathway as an explanation of their anti-proliferative effects. Sphingolipids were measured using liquid chromatography tandem mass spectrometry. Treatment of various cancer cell lines with celecoxib significantly increased sphinganine, C 16:0 -, C 24:0 -, C 24:1 -dihydroceramide (dhCer) and led to a depletion of C 24:0 -, C 24:1 -Cer in a time-and concentrationdependent manner, whereas other coxibs had no effect. Using 13 C, 15 N-labeled L-serine, we demonstrated that the augmented dhCers after celecoxib treatment originate from de novo synthesis. Celecoxib inhibited the dihydroceramide desaturase (DEGS) in vivo with an IC 50 of 78.9 6 1.5 mM and increased total Cer level about 2-fold, indicating an activation of sphingolipid biosynthesis. Interestingly, inhibition of the sphingolipid biosynthesis by specific inhibitors of L-serine palmitoyltransferase diminished the anti-proliferative potency of celecoxib. In conclusion, induction of de novo synthesis of sphingolipids and inhibition of DEGS contribute to the anti-proliferative effects of celecoxib.-Schiffmann, S., J. Sandner, R. Schmidt, K. Birod, I. Wobst, H. Schmidt, C. Angioni, G. Geisslinger, and S. Grösch. The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis. J. Lipid Res. 2009. 50: 32-40. Supplementary key words cancerSphingolipids constitute an essential component of the eucaryotic plasma membrane and are also utilized as an important second messenger in a variety of cellular events, including cell senescence, cellular differentiation, apoptosis, and proliferation (1-3). Endogenous sphingolipid levels can be controlled by activation of sphingomyelinases (SMases) and de novo synthesis as well as by specific degradation mechanisms (e.g., ceramidases, lyases). The sphingolipid biosynthesis commences in the endoplasmic reticulum with the condensation of palmitoyl-CoA and L-serine by L-serine palmitoyltransferase (L-SPT). The intermediate 3-ketosphinganine is rapidly converted into sphinganine (dhSph) by 3-ketosphinganine reductase. Acyl-CoA thioesters of variable chain lengths are then attached to dhSph by chain-length-specific (dihydro)ceramide synthases (CerSs) (4). Dihydroceramide desaturase (DEGS) introduces a 4, 5-trans double bond in dihydroceramides (dhCers), resulting in formation of the final product, Cer. Via sphingosine (Sph), Cer is metabolized by the enzymes ceramidase and sphingosine kinase to sphingosine-1-phosphate (Sph1P

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Ceramide metabolite, not intact ceramide molecule, may be responsible for cellular toxicity

Cited by 37 publications

References 31 publications

Effects of ceramide-1-phosphate on cultured cells: dependence on dodecane in the vehicle

Effects of ceramide-1-phosphate on cultured cells: dependence on dodecane in the vehicle

γ-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis

The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis

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