(Glyco)sphingolipidology: an amazing challenge and opportunity for systems biology

Merrill, Alfred H.; Wang, May D.; Park, Meeyoung; Sullards, M. Cameron

doi:10.1016/j.tibs.2007.09.004

Cited by 117 publications

(126 citation statements)

References 85 publications

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“…Since, GCS is over-expressed in almost all types of multidrug resistant cancer cells, it has been suggested as a potential marker of drug resistance [11,12]. In addition to GCS's roles in regulating proliferation and oncogenic transformation, it was shown that certain anticancer agents induce apoptosis through downregulating expression levels of GCS [13].…”

Section: Introductionmentioning

confidence: 99%

Bioactive sphingolipids in docetaxel-induced apoptosis in human prostate cancer cells

Bassoy

Baran

2012

Biomedicine & Pharmacotherapy

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In this study, we examined the possible roles of ceramide/sphingosine-1-phosphate and ceramide/glucosyleceramide signaling in docetaxel-induced apoptosis by examining expression levels of the glucosyleceramide synthase and sphingosine kinase-1 and ceramide synthase gene family. As confirmed by isobologram analysis, docetaxel in combination with agents that increase intracellular ceramide levels increased the cytotoxic and apoptotic effects of docetaxel synergistically. More importantly, RT-PCR results revealed that expression levels of glucosyleceramide synthase and sphingosine kinase-1 were downregulated and ceramide synthase genes were upregulated in response to docetaxel. This study identifies mechanisms underlying the involvement of ceramide metabolizing genes in docetaxel-induced apoptosis in prostate cancer cells. © 2012 Elsevier Masson SAS.TUBITAK project number 109S215 and Turkish Academy of Sciences Outstanding Young Investigator Programm

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Section: Introductionmentioning

confidence: 99%

Bioactive sphingolipids in docetaxel-induced apoptosis in human prostate cancer cells

Bassoy

Baran

2012

Biomedicine & Pharmacotherapy

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“…Ceramides are perhaps the most well studied class of SLs, because of their essential roles in differentiation and in apoptosis (5)(6)(7). Ceramides can differ in both their long chain sphingoid base (8) and fatty acid composition (9). Over the past few years, a complex mode of regulation of ceramide synthesis has been described, with each of the six mammalian ceramide synthase (CerS) (formerly known as Lass (longevity assurance)) genes generating ceramides with specific acyl chain lengths (10).…”

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confidence: 99%

A Critical Role for Ceramide Synthase 2 in Liver Homeostasis

Pewzner-Jung

Park

Laviad

et al. 2010

Journal of Biological Chemistry

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Ceramide is an important lipid signaling molecule that plays critical roles in regulating cell behavior. Ceramide synthesis is surprisingly complex and is orchestrated by six mammalian ceramide synthases, each of which produces ceramides with restricted acyl chain lengths. We have generated a CerS2 null mouse and characterized the changes in the long chain base and sphingolipid composition of livers from these mice. Ceramide and downstream sphingolipids were devoid of very long (C22-C24) acyl chains, consistent with the substrate specificity of CerS2 toward acyl-CoAs. Unexpectedly, C16-ceramide levels were elevated, and as a result, total ceramide levels were unaltered; however, C16-ceramide synthesis in vitro was not increased. Levels of sphinganine were also significantly elevated, by up to 50-fold, reminiscent of the effect of the ceramide synthase inhibitor, fumonisin B1. With the exceptions of glucosylceramide synthase and neutral sphingomyelinase 2, none of the other enzymes tested in either the sphingolipid biosynthetic or degradative pathways were significantly changed. Total glycerophospholipid and cholesterol levels were unaltered, although there was a marked elevation in C18:1 and C18:2 fatty acids in phosphatidylethanolamine, concomitant with a reduction in C18:0 and C20:4 fatty acids. Finally, differences were observed in the biophysical properties of lipid extracts isolated from liver microsomes, with membranes from CerS2 null mice displaying higher membrane fluidity and showing morphological changes. Together, these results demonstrate novel modes of cross-talk and regulation between the various branches of lipid metabolic pathways upon inhibition of very long acyl chain ceramide synthesis.Biological membranes contain thousands of different lipid species that can be broadly classified according to their backbone structure (1). Of these, sphingolipids (SL) 2 have become particularly prominent due to the discovery of their unexpected structural complexity and their intricate modes of cellular trafficking and metabolism (2-4). Ceramides are perhaps the most well studied class of SLs, because of their essential roles in differentiation and in apoptosis (5-7). Ceramides can differ in both their long chain sphingoid base (8) and fatty acid composition (9). Over the past few years, a complex mode of regulation of ceramide synthesis has been described, with each of the six mammalian ceramide synthase (CerS) (formerly known as Lass (longevity assurance)) genes generating ceramides with specific acyl chain lengths (10). Thus, CerS1 uses mostly C18-CoA (11); CerS4 uses C18-and C20-CoAs (12); CerS5 and CerS6 use mostly C16-CoA (12, 13); and CerS3 uses very long chain acyl-CoAs (C26 and higher) (14). CerS2 can utilize a wider range of fatty acyl-CoAs but uses mainly C22 to C24. In addition, CerS2 displays complex modes of regulation and has genomic features characteristic of a "housekeeping" gene, although no other CerS genes display these characteristics (15).We have now generated a CerS2 null mouse and have ...

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“…6 Sphingolipids are also known as regulators of cell proliferation, differentiation, autophagy, cellular interactions, migration, signaling, and cell death. 28 Mammalian sphingolipids are Error in Da has been provided from theoretical data. Average standard normalized dataset is presented here.…”

Section: Discussionmentioning

confidence: 99%

“…Other sphingolipids such as sphingosine arise through degradation pathways. 28 The sphingolipids may be synthesized using various different enzymatic pathways (Fig. 3).…”

mentioning

confidence: 99%

A Comparison of Trabecular Meshwork Sphingolipids and Ceramides of Ocular Normotensive and Hypertensive States of DBA/2J Mice

Guerra

Aljohani

Edwards

et al. 2014

Journal of Ocular Pharmacology and Therapeutics

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Purpose: To determine the differential profiles of sphingomyelin, sphingoid base, sphingoid base-1-phosphate, and ceramide and their quantitative differences between trabecular meshwork (TM) derived from normotensive and hypertensive intraocular pressure states of DBA/2J mice. Methods: Normotensive and hypertensive state TM were collected from mice and analyzed. Lipid extraction was performed using the Bligh and Dyer method, and the protein concentrations were determined using the Bradford method. The lipids were identified and quantified using appropriate standards with a TSQ Quantum Access Max triple quadrupole mass spectrometer applying class-specific lipid identification settings. Results: The comparative profiles of sphingomyelin, sphingoid base, sphingoid base-1-phosphate, and ceramide between normotensive and hypertensive TM showed several species unique to a phase and as well common between states. Conclusion: The presence or absence of several sphingolipids and ceramides in the normotensive or hypertensive states may contribute to better understanding of the glaucomas.

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(Glyco)sphingolipidology: an amazing challenge and opportunity for systems biology

Cited by 117 publications

References 85 publications

Bioactive sphingolipids in docetaxel-induced apoptosis in human prostate cancer cells

Bioactive sphingolipids in docetaxel-induced apoptosis in human prostate cancer cells

A Critical Role for Ceramide Synthase 2 in Liver Homeostasis

A Comparison of Trabecular Meshwork Sphingolipids and Ceramides of Ocular Normotensive and Hypertensive States of DBA/2J Mice

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