PT  - JOURNAL ARTICLE
AU  - Anne Gomez-Brouchet
AU  - Dimitri Pchejetski
AU  - Leyre Brizuela
AU  - Virginie Garcia
AU  - Marie-Françoise Altié
AU  - Marie-Lise Maddelein
AU  - Marie-Bernadette Delisle
AU  - Olivier Cuvillier
TI  - Critical Role for Sphingosine Kinase-1 in Regulating Survival of Neuroblastoma Cells Exposed to Amyloid-β Peptide
AID  - 10.1124/mol.106.033738
DP  - 2007 Aug 01
TA  - Molecular Pharmacology
PG  - 341--349
VI  - 72
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/72/2/341.short
4100  - http://molpharm.aspetjournals.org/content/72/2/341.full
SO  - Mol Pharmacol2007 Aug 01; 72
AB  - 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 β (Aβ) peptide (25-35). Upon incubation with Aβ, 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 Aβ-induced cell death. SphK1 overexpression impaired the cytotoxicity of Aβ, whereas SphK1 silencing by RNA interference mimicked Aβ-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 Aβ 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-β1 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 Aβ-treated cells.