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

Gomez-Brouchet, Anne, Pchejetski, Dmitry, Brizuela, Leyre, Garcia, Virginie, Altié, Marie-Françoise, Maddelein, Marie-Lise, Delisle, Marie-Bernadette and Cuvillier, Olivier (2007) Critical role for sphingosine kinase-1 in regulating survival of neuroblastoma cells exposed to amyloid-beta peptide. Molecular Pharmacology, 72 (2). pp. 341-9. ISSN 0026-895X

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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.

Item Type: Article
Uncontrolled 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
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 16 Dec 2014 10:06
Last Modified: 25 Jul 2018 10:20
URI: https://ueaeprints.uea.ac.uk/id/eprint/51542
DOI: 10.1124/mol.106.033738

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