3-Ketosphinganine provokes the accumulation of dihydroshingolipids and induces autophagy in cancer cells.
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| 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.
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| Authors | Yadira F Ordóñez, Jèssica González, Carmen Bedia, Josefina Casas, José Luis Abad, Antonio Delgado, Gemma Fabrias |
| Journal | Molecular bioSystems (Mol Biosyst) Vol. 12 Issue 4 Pg. 1166-73 (Apr 2016) ISSN: 1742-2051 [Electronic] England |
| PMID | 26928714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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