Received for publication December 22, 2006.
Revised May 22, 2007.
Accepted for publication May 22, 2007.

CRITICAL ROLE FOR SPHINGOSINE KINASE-1 IN REGULATING SURVIVAL OF NEUROBLASTOMA CELLS EXPOSED TO AMYLOID- 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 A peptide (25-35). Upon incubation with A, 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 as N-acetylcysteine totally abrogated the down-regulation of SphK1 activity and strongly inhibited A-induced cell death. SphK1 overexpression impaired the cytoxicity of A while SphK1 silencing by RNA interference mimicked A-induced cell death hence establishing a critical role for SphK1. We further demonstrated that SphK1 could mediate the well-established cytoprotective action of IGF-I against A 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-1 was also dependent on SphK1 activity as activation of SphK1 as well as cell survival were impeded by a dominant-negative form of SphK1. Collectively, these results provide the first illustration of SphK1 role as a critical regulator of death and survival of A-treated cells.

Key words: Growth hormone, Sphingolipids, Apoptosis, Oxidative stress/antioxidants