Sustained activation of sphingomyelin synthase by 2-hydroxyoleic acid induces sphingolipidosis in tumor cells.

J Lipid Res. 2013 May;54(5):1457-65.

Martin ML, Liebisch G, Lehneis S, Schmitz G, Alonso-Sande M, Bestard-Escalas J, Lopez DH, García-Verdugo JM, Soriano-Navarro M, Busquets X, Escribá PV, Barceló-Coblijn G.

Laboratory of Molecular Cell Biomedicine, Department of Biology, University Institute for Research into Health Sciences (IUNICS), University of the Balearic Islands, E-07122 Palma, Balearic Islands, Spain.

Abstract

The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor drug, involves the rapid and specific activation of sphingomyelin synthase (SMS), leading to a 4-fold increase in SM mass in tumor cells. In the present study, we investigated the source of the ceramides required to sustain this dramatic increase in SM. Through radioactive and fluorescent labeling, we demonstrated that sphingolipid metabolism was altered by a 24 h exposure to 2OHOA, and we observed a consistent increase in the number of lysosomes and the presence of unidentified storage materials in treated cells. Mass spectroscopy revealed that different sphingolipid classes accumulated in human glioma U118 cells after exposure to 2OHOA, demonstrating a specific effect on C16-, C20-, and C22-containing sphingolipids. Based on these findings, we propose that the demand for ceramides required to sustain the SMS activation (ca. 200-fold higher than the basal level) profoundly modifies both sphingolipid and phospholipid metabolism. As the treatment is prolonged, tumor cells fail to adequately metabolize sphingolipids, leading to a situation resembling sphingolipidosis, whereby cell viability is compromised.

PMID: 23471028

 

Gwendolyn Barceló-Coblijn-1

The model depicts our current view of the lipid changes in the effects of 2OHOA against tumors. The sustained SMS activation by 2OHOA (1) increases the SM content at the plasma membrane leading to the deregulation of the sphingolipid metabolism evidenced by the activation of both the de novo synthesis and the salvage pathway (2). As the treatment is prolonged, tumor cells fail to adequately metabolize sphingolipids, leading to a situation resembling sphingolipidosis. In addition, 2OHOA provokes a profound remodeling of the cell fatty acid composition mainly caused by the incorporation of 2OHOA into the glycerolipids and glycerophospholipids fractions (3). All together, these lipid changes affect the lipid raft properties as well as raft dependent signaling pathways.

Abbreviation: 1,2-DAG: 1,2-diacylglyerol, Cer: ceramides, GluCer: glucosylceramide, SM: sphingomyelin, SMS1: sphingomyelin synthase 1, SMS2: sphingomyelin synthase 2, Sph: sphingosine, Spa: sphinganine,-

Reference:

1. Barceló-Coblijn G, Martin ML, de Almeida RF, Noguera-Salvà MA, Marcilla-Etxenike A, Guardiola-Serrano F, Lüth A, Kleuser B, Halver JE, Escribá PV (2011) Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy. Proc Natl Acad Sci U S A 108: 19569-19574

2. Martin ML, Barceló-Coblijn G, de Almeida RF, Noguera-Salvà MA, Teres S, Higuera M, Liebisch G, Schmitz G, Busquets X, Escribá PV (2013a) The role of membrane fatty acid remodeling in the antitumor mechanism of action of 2-hydroxyoleic acid. Biochim Biophys Acta 1828: 1405-1413

3. Martin ML, Liebisch G, Lehneis S, Schmitz G, Alonso-Sande M, Bestard-Escalas J, López DH, García-Verdugo JM, Soriano-Navarro M, Busquets X, Escribá PV, Barceló-Coblijn G (2013b) Sustained activation of sphingomyelin synthase by 2-hydroxyoleic acid induces sphingolipidosis in tumor cells. J Lipid Res 54: 1457-1465

 

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