Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

Holthuis, Joost C. M.; Luberto, Chiara

doi:10.1007/978-1-4419-6741-1_5

Cited by 38 publications

(22 citation statements)

References 91 publications

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“…Because AC is a lysosomal enzyme and ceramides cannot exit from the lysosome ( 46 ), a lack of AC activity leads to an intralysosomal accumulation of ceramide. However, sphingomyelin synthase 2 is localized in the plasma membrane, whereas sphingomyelin synthase 1 and glucosylceramide synthase reside in the Golgi apparatus ( 14,47 ). the PC-3/Mc cell line.…”

Section: Discussionmentioning

confidence: 99%

“…These two isoforms differ in temporal patterns of expression during development, are expressed in different tissues, and possess distinct kinetic properties ( 13 ), implying that they perform different cellular functions. Ceramide may also be converted back to SM by transfer of phosphorylcholine from phosphatidylcholine via SM synthases ( 14 ). Alternatively, it can be glycosylated by glucosylceramide synthase to form glucosylceramide, which may be further modifi ed by various enzymes in the Golgi apparatus to form complex glycosphingolipids ( 15 ).…”

Section: Papain Activitymentioning

confidence: 99%

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Acid ceramidase as a therapeutic target in metastatic prostate cancer

Camacho

Meca-Cortés

Abad

et al. 2013

Journal of Lipid Research

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Supplementary key words ceramide • metastasis • inhibitorsCancer cells develop a lipogenic phenotype that supports the energy and membrane synthesis requirements associated with the enhanced proliferation and survival under stress inherent to malignant progression ( 1, 2 ). The recognition of the importance of this phenotype in cancer has led to the use of enzymes of lipid metabolism as markers to monitor neoplastic progression and response to therapy, as well as to the development of drugs targeted at key lipogenic enzymes, such as fatty acid synthase (FASN) ( 2, 3 ). The excess fatty acid synthesis that results from the coordinated activation of lipogenic enzymes in many types of cancer leads to the accumulation of palmitate, which needs to be further processed by the cells due to the toxic effects of its accumulation. One pathway that Abstract Acid ceramidase (AC) catalyzes the hydrolysis of ceramide into sphingosine, in turn a substrate of sphingosine kinases that catalyze its conversion into the mitogenic sphingosine-1-phosphate. AC is expressed at high levels in several tumor types and has been proposed as a cancer therapeutic target. Using a model derived from PC-3 prostate cancer cells, the highly tumorigenic, metastatic, and chemoresistant clone PC-3/Mc expressed higher levels of the AC ASAH1 than the nonmetastatic clone PC-3/S. Stable knockdown of ASAH1 in PC-3/Mc cells caused an accumulation of ceramides, inhibition of clonogenic potential, increased requirement for growth factors, and inhibition of tumorigenesis and lung metastases. We developed de novo ASAH1 inhibitors, which also caused a dose-dependent accumulation of ceramides in PC-3/Mc cells and inhibited their growth and clonogenicity. Finally, immunohistochemical analysis of primary prostate cancer samples showed that higher levels of ASAH1 were associated with more advanced stages of this neoplasia. These observations confi rm ASAH1 as a therapeutic target in advanced and chemoresistant forms of prostate cancer and suggest that our new potent and specifi c AC inhibitors could act by counteracting critical growth properties of SAF2008-00706 and SAF2011-22444 (to G.F.) Press, February 18, 2013 DOI 10.1194 Acid ceramidase as a therapeutic target in metastatic prostate cancer Abbreviations: AC, acid ceramidase; CMH, ceramide monohexoside; MDR1, multidrug resistant protein 1; NC, neutral ceramidase; PC, prostate cancer; PIN, prostate intraepithelial neoplasia; S1P, sphingosine-1-phosphate. This work was supported by Ministry of Science and Innovation Grants ; Agència de Gestió d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya Grant 2009SGR1072 (to G.F.); Ministry of Science and Innovation Grants SAF2008-04136-C02-01 and SAF2011-24686 (to T.M.T.); Ministry of Economy and Competitivity Grant SAF2012-40017-C02-01 (to T.M.T.); Agència de Gestió d'Ajuts Universitaris i de Recerca de la Generalitat de Catalunya Grant 2009SGR1482 (to T.M.T.); Xarxa de Bancs de Tumours de Catalunya-Pla Director d'Oncologia and Fondo Europeo de Desarrollo...

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Section: Discussionmentioning

confidence: 99%

Section: Papain Activitymentioning

confidence: 99%

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Camacho

Meca-Cortés

Abad

et al. 2013

Journal of Lipid Research

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“…The presence of SM increases the rigidity and compactness of the plasma membrane (PM). Moreover, SM is found to be associated with cholesterol, further packing the PM, and defining rigid platforms, which have been thought to cluster certain proteins, such as a membrane receptors (Holthuis and Luberto, 2010;Lingwood et al, 2009;Simons and Ikonen, 1997).…”

Section: De Novo Synthesismentioning

confidence: 98%

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

Adada

Luberto

Canals

2016

Chemistry and Physics of Lipids

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“…A reduction in SM can promote net transfer of phosphocholine from phosphatidylcholine to ceramide to replace the sphingomyelin, resulting in an increase in membrane DAG (2010). This fully reversible reaction is catalyzed in the plasma membrane by SMS2 (sphingomyelin synthase 2, also known as SGMS2) (779,1735). SMS1, a counterpart to SMS2, is found primarily in the Golgi.…”

Section: Abca1 Is a Signaling Hub As Well As A Cholesterol And Phosphmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Tales and Mysteries of the Enigmatic Sphingomyelin Synthase Family

Cited by 38 publications

References 91 publications

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

Molecular Biology of Atherosclerosis

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