title: Sustained activation of sphingomyelin synthase by 2-hydroxyoleic acid induces sphingolipidosis in tumor cells.
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.
authors.affiliation: 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.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Martin
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.forename: Stefan
authors.initials: S
authors.lastname: Lehneis
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
authors.forename: María
authors.initials: M
authors.lastname: Alonso-Sande
authors.forename: Joan
authors.initials: J
authors.lastname: Bestard-Escalas
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Lopez
authors.forename: José Manuel
authors.initials: JM
authors.lastname: García-Verdugo
authors.forename: Mario
authors.initials: M
authors.lastname: Soriano-Navarro
authors.forename: Xavier
authors.initials: X
authors.lastname: Busquets
authors.forename: Pablo V
authors.initials: PV
authors.lastname: Escribá
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Barceló-Coblijn
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009829:Oleic Acids / Q000494:pharmacology*; D013106:Sphingolipidoses / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D013107:Sphingolipids / Q000378:metabolism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000378:metabolism*
chemical_list: C483229:2-hydroxyoleic acid; D002518:Ceramides; D009829:Oleic Acids; D013107:Sphingolipids; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase