title: Critical role for sphingosine kinase-1 in regulating survival of neuroblastoma cells exposed to amyloid-beta peptide.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Gomez-Brouchet
authors.forename: Dimitri
authors.initials: D
authors.lastname: Pchejetski
authors.forename: Leyre
authors.initials: L
authors.lastname: Brizuela
authors.forename: Virginie
authors.initials: V
authors.lastname: Garcia
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Altié
authors.forename: Marie-Lise
authors.initials: ML
authors.lastname: Maddelein
authors.forename: Marie-Bernadette
authors.initials: MB
authors.lastname: Delisle
authors.forename: Olivier
authors.initials: O
authors.lastname: Cuvillier
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000099157:Sphingosine Kinase
chemical_list: D016229:Amyloid beta-Peptides; D007334:Insulin-Like Growth Factor I; D010446:Peptide Fragments; D017853:Phosphotransferases (Alcohol Group Acceptor); D053773:Transforming Growth Factor beta1; D000099157:Sphingosine Kinase; C074636:amyloid beta-protein (25-35)