title: 3-Ketosphinganine provokes the accumulation of dihydroshingolipids and induces autophagy in cancer cells.
abstract: Although several reports describe the metabolic fate of sphingoid bases and their analogs, as well as their action and that of their phosphates as regulators of sphingolipid metabolizing-enzymes, similar studies for 3-ketosphinganine (KSa), the product of the first committed step in de novo sphingolipid biosynthesis, have not been reported. In this article we show that 3-ketosphinganine (KSa) and its dideuterated analog at C4 (d2KSa) are metabolized to produce high levels of dihydrosphingolipids in HGC27, T98G and U87MG cancer cells. In contrast, either direct C1 O-phosphorylation or N-acylation of d2KSa to produce dideuterated ketodihydrosphingolipids does not occur. We also show that cells respond to d2KSa treatment with induction of autophagy. Time-course experiments agree with sphinganine, sphinganine 1-phosphate and dihydroceramides being the mediators of autophagy stimulated by d2KSa. Enzyme inhibition studies support that inhibition of Des1 by 3-ketobases is caused by their dihydroceramide metabolites. However, this effect contributes to increasing dihydrosphingolipid levels only at short incubation times, since cells respond to long time exposure to 3-ketobases with Des1 overexpression. The translation of these overall effects into cell fate is discussed.
authors.affiliation: Consejo Superior de Investigaciones Científicas (CSIC), Institut de Química Avançada de Catalunya (IQAC-CSIC), Research Unit on Bioactive Molecules (RUBAM), Jordi Girona 18-26, 08034 Barcelona, Spain. gemma.fabrias@iqac.csic.es.
authors.forename: Yadira F
authors.initials: YF
authors.lastname: Ordóñez
authors.forename: Jèssica
authors.initials: J
authors.lastname: González
authors.forename: Carmen
authors.initials: C
authors.lastname: Bedia
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: José Luis
authors.initials: JL
authors.lastname: Abad
authors.forename: Antonio
authors.initials: A
authors.lastname: Delgado
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabrias
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D053858:Metabolic Networks and Pathways; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C002882:ketodihydrosphingosine; D010088:Oxidoreductases; D013110:Sphingosine