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Title: | 3-Ketosphinganine provokes the accumulation of dihydroshingolipids and induces autophagy in cancer cells. |
Authors: | Ordoñez, Yadira F.; González, Jèssica; Bedia, Carmen ![]() ![]() ![]() ![]() ![]() |
Keywords: | Metabolic fate 3-ketosphinganine KSa Enzyme inhibition Dihydroceramide metabolites |
Issue Date: | 22-Apr-2016 |
Publisher: | Royal Society of Chemistry (UK) |
Citation: | Molecular BioSystems 12(4): 1166-1173 (2016) |
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. |
Publisher version (URL): | http://dx.doi.org/10.1039/c5mb00852b. |
URI: | http://hdl.handle.net/10261/130514 |
DOI: | 10.1039/c5mb00852b |
Appears in Collections: | (IQAC) Artículos |
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