Control of metabolism and signaling of simple bioactive sphingolipids: Implications in disease

Gangoiti, Patricia; Camacho, Luz; Arana, Lide; Ouro, Alberto; Granado, María H.; Brizuela, Leyre; Casas, Josefina; Fabriás, Gemma; Abad, José Luı́s; Delgado, Antonio; Gómez-Muñoz, Antonio

doi:10.1016/j.plipres.2010.02.004

Cited by 124 publications

(93 citation statements)

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“…For example, CERS6-dependent elevation of C16-ceramide is associated with obesity and insulin resistance (42), and mutations in the ASAH1 gene, which encodes acid ceramidase, cause Farber disease due to accumulation of ceramides in lysosomes (4,43). Reducing ceramide synthesis by the inhibition of CERS phosphorylation may be a potential option to treat such diseases.…”

Section: Discussionmentioning

confidence: 99%

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

Sassa

Hirayama

Kihara

2016

Journal of Biological Chemistry

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Ceramide and complex sphingolipids regulate important cellular functions including cell growth, apoptosis, and signaling. Dysregulation of sphingolipid metabolism leads to pathological consequences such as sphingolipidoses and insulin resistance. Ceramides in mammals vary greatly in their acyl-chain composition: six different ceramide synthase isozymes (CERS1-6) that exhibit distinct substrate specificity and tissue distribution account for this diversity. In the present study, we demonstrated that CERS2-6 were phosphorylated at the cytoplasmic C-terminal regions. Most of the phosphorylated residues conformed to a consensus motif for phosphorylation by casein kinase 2 (CK2), and treatment of cells with the CK2-specific inhibitor CX-4945 lowered the phosphorylation levels of CERS2, -4, -5, and -6. Phosphorylation of CERS2 was especially important for its catalytic activity, acting mainly by increasing its V max value. Phosphorylation modestly increased the catalytic activities of CERS4 and -5 and mildly increased those of CERS3 and -6. Dephosphorylation of endogenous ceramide synthases in the mouse brain led to severely reduced activity toward the Cers2 substrates C22:0/C24:0-CoAs and modestly reduced activity toward the Cers5/6 substrate C16:0-CoA. These results suggest that the phosphorylation of ceramide synthases may be a key regulatory point in the control of the distribution and levels of sphingolipids of various acyl-chain lengths.Sphingolipids, one of the major lipid constituents of eukaryotic membranes, mediate a number of cellular and physiological functions such as cell growth, apoptosis, immune responses, and the epidermal permeability barrier, whereas their abnormal metabolism is involved in diseases such as sphingolipidoses, neural disorders, and diabetes (1-7). Ceramides are located in the hub of sphingolipid metabolism. Ceramides are precursors for complex sphingolipids, whereas their hydrolysis releases a sphingoid long-chain base and a fatty acid (FA).2 The released long-chain base can then be recycled to synthesize new ceramide, or metabolized further into other lipids such as sphingosine 1-phosphate (8 -10). Ceramide synthases catalyze the formation of an amide bond between the long-chain base and the FA in the endoplasmic reticulum. In most tissues, the chain lengths of the FA moieties of ceramides are C16 -

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Section: Discussionmentioning

confidence: 99%

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

Sassa

Hirayama

Kihara

2016

Journal of Biological Chemistry

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“…The growing recognition of AC as a potential therapeutic target in cancer has encouraged the development of AC inhibitors ( 12 ). AC belongs to the N -terminal nucleophile (Ntn) hydrolase family ( 48 ).…”

Section: Discussionmentioning

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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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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“…Human ceramidase, localized to the Golgi complex in human HeLa cells, controls the hydrolysis of ceramides (Xu et al 2006). Ceramidases are also concentrated in particular tissues, overexpressed in several cancer cell lines and cancer tissues (Gangoiti et al 2010) including HeLa cells (Sun et al 2009). In cultured neural cells, both C18 and C20 sphingosines were detected (Valsecchi et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Human tRNA^Secassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers

Janas

Yarus

2012

RNA

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We have shown previously that simple RNA structures bind pure phospholipid liposomes. However, binding of bona fide cellular RNAs under physiological ionic conditions is shown here for the first time. Human tRNA Sec contains a hydrophobic anticodon-loop modification: N 6 -isopentenyladenosine (i 6 A) adjacent to its anticodon. Using a highly specific double-probe hybridization assay, we show mature human tRNA Sec specifically retained in HeLa intermediate-density membranes. Further, isolated human tRNA Sec rebinds to liposomes from isolated HeLa membrane lipids, to a much greater extent than an unmodified tRNA Sec transcript. To better define this affinity, experiments with pure lipids show that liposomes forming rafts or including positively charged sphingosine, or particularly both together, exhibit increased tRNA Sec binding. Thus tRNA Sec residence on membranes is determined by several factors, such as hydrophobic modification (likely isopentenylation of tRNA Sec ), lipid structure (particularly lipid rafts), or sphingosine at a physiological concentration in rafted membranes. From prior work, RNA structure and ionic conditions also appear important. tRNA Sec dissociation from HeLa liposomes implies a mean membrane residence of 7.6 min at 24°C (t 1 ⁄ 2 = 5.3 min). Clearly RNA with a 5-carbon hydrophobic modification binds HeLa membranes, probably favoring raft domains containing specific lipids, for times sufficient to alter biological fates.

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Control of metabolism and signaling of simple bioactive sphingolipids: Implications in disease

Cited by 124 publications

References 288 publications

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Human tRNA^Secassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers

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Control of metabolism and signaling of simple bioactive sphingolipids: Implications in disease

Cited by 124 publications

References 288 publications

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

Enzyme Activities of the Ceramide Synthases CERS2–6 Are Regulated by Phosphorylation in the C-terminal Region

Acid ceramidase as a therapeutic target in metastatic prostate cancer

Human tRNASecassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers

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Human tRNA^Secassociates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers