Critical role for sphingosine kinase-1 in regulating survival of neuroblastoma cells exposed to amyloid-beta peptide

Anne Gomez-Brouchet, Dmitry Pchejetski, Leyre Brizuela, Virginie Garcia, Marie-Françoise Altié, Marie-Lise Maddelein, Marie-Bernadette Delisle, Olivier Cuvillier

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50 Citations (Scopus)

Abstract

We examined the role of sphingosine kinase-1 (SphK1), a critical regulator of the ceramide/sphingosine 1-phosphate (S1P) biostat, in the regulation of death and survival of SH-SY5Y neuroblastoma cells in response to amyloid beta (Abeta) peptide (25-35). Upon incubation with Abeta, SH-SY5Y cells displayed a marked down-regulation of SphK1 activity coupled with an increase in the ceramide/S1P ratio followed by cell death. This mechanism was redox-sensitive; N-acetylcysteine totally abrogated the down-regulation of SphK1 activity and strongly inhibited Abeta-induced cell death. SphK1 overexpression impaired the cytotoxicity of Abeta, whereas SphK1 silencing by RNA interference mimicked Abeta-induced cell death, thereby establishing a critical role for SphK1. We further demonstrated that SphK1 could mediate the well established cytoprotective action of insulin-like growth factor (IGF-I) against Abeta toxicity. A dominant-negative form of SphK1 or its pharmacological inhibition not only abrogated IGF-I-triggered stimulation of SphK1 but also hampered IGF-I protective effect. Similarly to IGF-I, the neuroprotective action of TGF-beta1 was also dependent on SphK1 activity; activation of SphK1 as well as cell survival were impeded by a dominant-negative form of SphK1. Taken together, these results provide the first illustration of SphK1 role as a critical regulator of death and survival of Abeta-treated cells.
Original languageEnglish
Pages (from-to)341-9
Number of pages9
JournalMolecular Pharmacology
Volume72
Issue number2
DOIs
Publication statusPublished - Aug 2007

Keywords

  • Amyloid beta-Peptides
  • Cell Line
  • Cell Survival
  • Humans
  • Insulin-Like Growth Factor I
  • Neuroblastoma
  • Peptide Fragments
  • Phosphotransferases (Alcohol Group Acceptor)
  • Transforming Growth Factor beta1

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