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

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 t...

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Bibliographic Details
Published in:Journal of lipid research 2013-05, Vol.54 (5), p.1457-1465
Main Authors: Martin, Maria Laura, Liebisch, Gerhard, Lehneis, Stefan, Schmitz, Gerd, Alonso-Sande, María, Bestard-Escalas, Joan, Lopez, Daniel H, García-Verdugo, José Manuel, Soriano-Navarro, Mario, Busquets, Xavier, Escribá, Pablo V, Barceló-Coblijn, Gwendolyn
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Cell Survival - drug effects
Ceramides - metabolism
Ceramides - pharmacology
Glioma - metabolism
Glioma - pathology
Humans
Oleic Acids - pharmacology
Sphingolipidoses - chemically induced
Sphingolipidoses - metabolism
Sphingolipidoses - pathology
Sphingolipids - metabolism
Transferases (Other Substituted Phosphate Groups) - metabolism
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Summary: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.
ISSN:0022-2275
1539-7262
DOI:10.1194/jlr.M036749