Dihydroceramide desaturase activity is modulated by oxidative stress

Idkowiak‐Baldys, Jolanta; Apraiz, Aintzane; Li, Li; Rahmaniyan, Mehrdad; Clarke, Christopher J.; Kraveka, Jacqueline M.; Asumendi, Aintzane; Hannun, Yusuf A.

doi:10.1042/bj20091589

Cited by 48 publications

(53 citation statements)

References 36 publications

(44 reference statements)

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“…These results suggest that autophagy induced by SKI II is actually due to increases in dhCer rather than to decreased production of S1P, which occurs with both SKI II and PF543. Furthermore, increase in LC3 II was also the enzyme environment, which has been reported to affect this enzymatic activity ( 75 ). SKI II is a nonstructural analog of Des1 substrate and, as such, it does not probably directly interact with the Des1 protein.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani

Casasampere

Sanllehí

et al. 2014

Journal of Lipid Research

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proapoptotic sphingosine (So) and ceramide (Cer). Thus, as central enzymes in modulating the Cer/S1P balance, SKs are attractive targets for cancer therapy ( 1 ). Two SKs exist in humans, SK1 and SK2. SK1 has been extensively studied and there is a large body of evidence that proves its role in promoting cell survival, proliferation, and neoplastic transformation ( 2-5 ). SK1 is also elevated in many human cancers, which appears to contribute to carcinogenesis, chemotherapeutic resistance, and poor patient outcome. SK2, however, has not been as well-characterized, and there are contradictions in the key physiological functions that have been proposed for this isoform. Despite this, many studies are now emerging that implicate SK2 in key roles in a variety of diseases, including the development of a range of solid tumors ( 6 ).The potential of SKs as therapeutic targets has boosted the development of small molecule inhibitors ( 4,(7)(8)(9)(10)(11)(12)(13)(14). A detailed characterization of their pharmacology, particularly their selectivity against human SK1 and SK2, has been published ( 15 ). The fi rst known SK inhibitors were long chain base analogs such as N , N -dimethyl-D-erythro-sphingosine (DMS) ( 16,17 ) and L-threo-dihydrosphingosine (safi ngol) ( 18-21 ). While DMS inhibits both SK1 and SK2 by (SGR 2009(SGR 1072, and the Fundació la Marató de TV3 (112130 and 112132 Abbreviations: CB5R, NADH-cytochrome b5 reductase; C16dhCer, N -hexadecanoyldihydrosphingosine ; CDH, ceramide dihexoside (lactosylceramide); Cer, ceramide; CerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphingosine; CMH, ceramide monohexoside (glucosyl and galactosylceramide); Des1, dihydroceramide desaturase; dhCDH, dihydroceramide dihexoside (lactosyldihydroceramide); dhCer, dihydroceramide; dhCerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-dihydrosphingosine; dhSM, dihydrosphingomyelin; DMS, N , N -dimethyl-D-erythro-sphingosine; FAD, fl avin adenine dinucleotide; LC3, microtubule-associated protein 1-light chain 3; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; NBD, 4-nitro-2,1,3-benzoxadiazole; PDB, Protein Data Bank; S1P, sphingosine-1-phosphate; SK, sphingosine kinase; SKI, sphingosine kinase inhibitor; So, sphingosine; TBST, TBS with 0.1% Tween 20; UPLC, ultraperformance LC . This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-22444), the Generalitat de Catalunya

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Section: Discussionmentioning

confidence: 99%

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani

Casasampere

Sanllehí

et al. 2014

Journal of Lipid Research

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“…The authors suggested that sphingolipid changes resulting from dihydroceramide desaturase inhibition contribute to the COX2-independent, antiproliferating effect of celecoxib ( 19 ). Moreover, in a recent study, oxidative stress was shown to lead to accumulation of dihydroceramide due to dihydroceramide desaturase inhibition in several cell lines ( 21 ). Depletion of dihydroceramide desaturase by siRNA has shown to result in accumulation of dihydroceramides and G0/G1 cell-cycle arrest in neuroblastoma cells, suggesting a role for dihydroceramides in growth inhibition ( 10 ).…”

Section: Lipid Extraction and Mass Spectrometry Measurementsmentioning

confidence: 99%

“…On the other hand, until recently, the precursor of ceramide, dihydroceramide, was considered a bio-inert molecule, and a short-chain (C 2 ) dihydroceramide analog was used as a negative control in experiments to study the effects of ceramide ( 16,17 ). Recent studies using depletion or inhibition of dihydroceramide desaturase, which uses dihydroceramide as a substrate, changed the way we think about this concept ( 10,(18)(19)(20)(21)(22). Fenretinide and resveratrol treatments are reported to inhibit dihydroceramide desaturase and increase endogenous dihydroceramides, resulting in autophagy in cancer cells ( 10,20,22,23 ).…”

Section: Lipid Extraction and Mass Spectrometry Measurementsmentioning

confidence: 99%

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Cell density-dependent reduction of dihydroceramide desaturase activity in neuroblastoma cells

Spassieva

Rahmaniyan

Bielawski

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.orgIn the last two decades, sphingolipids and their precursors have been extensively studied for their cell signaling roles (recently reviewed in Ref. 1 ). Changes in sphingolipid levels are shown to play a role in regulating important cellular processes, such as cell proliferation, growth arrest, and cell death. Here we investigated the role of sphingolipids in cell-cycle arrest at high cell density, a phenomenon known as contact inhibition at saturation density ( 2 ). Density-dependent inhibition in cultured cells serves as a model to study the balance between cell proliferation and growth arrest in a multicellular organism. Cell-number control is important for maintenance of tissue homeostasis within multicellular organisms, and cell-cycle arrest is a critical aspect of that control mechanism ( 2, 3 ). Cell-cycle arrest at high saturation density is a complex process dependent on multiple factors, and earlier studies have shown that sphingolipids play a role in it. Gangliosides, GM 3 in particular, have been shown to promote growth inhibition in confl uent cells ( 2,4,5 ), and a recent study has revealed that abundance of another ganglioside, GM 1 , on the cellular membrane depends on the cell's population context ( 6 ). A more recent work showed that very long chain (VLC) ceramides (i.e., ceramides with fatty acid chain length C 22 -C 26 ) also play a role in cell-cycle arrest at contact inhibition in breast cancer cells ( 7 ).Changes in sphingolipids, resulting from various cellular insults or manipulation of the sphingolipid pathway, are often complex and include simultaneous changes of several sphingolipid species ( 1,8 ). Therefore, considering the interdependency of the sphingolipid pathway, we applied a metabolic approach to decipher the role of sphingolipids in density-dependent growth arrest in neuroblastoma cells. Neuroblastoma is the most common cancer in infants and understanding its biology is important for devising new therapeutic strategies.Abstract We applied a metabolic approach to investigate the role of sphingolipids in cell density-induced growth arrest in neuroblastoma cells. Our data revealed that sphingolipid metabolism in neuroblastoma cells signifi cantly differs depending on the cells' population context. At high cell density, cells exhibited G0/G1 cell-cycle arrest and reduced ceramide, monohexosylceramide, and sphingomyelin, whereas dihydroceramide was signifi cantly increased. In addition, our metabolic-labeling experiments showed that neuroblastoma cells at high cell density preferentially synthesized very long chain (VLC) sphingolipids and dramatically decreased synthesis of sphingosine-1-phosphate (S1P). Moreover, densely populated neuroblastoma cells showed increased message levels of both anabolic and catabolic enzymes of the sphingolipid pathway. Notably, our metabolic-labeling experiments indicated reduced dihydroceramide desaturase activity at confl uence, which was confi rmed by direct measurement of dihydroceramide desat...

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“…A link between SL metabolism and ROS generation has been reported (22)(23)(24)(25). We now analyze ROS production in CerS2 null mouse liver.…”

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confidence: 99%

Ablation of Ceramide Synthase 2 Causes Chronic Oxidative Stress Due to Disruption of the Mitochondrial Respiratory Chain

Zigdon

Kogot-Levin²,

Park

et al. 2013

Journal of Biological Chemistry

173

120

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Background: Ceramide synthase 2 null mice, which cannot synthesize very-long chain ceramides, display severe hepatopathy. Results: These mice have elevated sphinganine and altered N-acyl chain ceramides that disrupt mitochondrial function by modifying respiratory chain activity. Conclusion: Alteration of mitochondrial sphingolipids results in formation of reaction oxygen species in liver. Significance: Ceramides with defined acyl chains influence oxidative stress signaling pathways.

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Dihydroceramide desaturase activity is modulated by oxidative stress

Cited by 48 publications

References 36 publications

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cell density-dependent reduction of dihydroceramide desaturase activity in neuroblastoma cells

Ablation of Ceramide Synthase 2 Causes Chronic Oxidative Stress Due to Disruption of the Mitochondrial Respiratory Chain

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