Critical Role for Sphingosine Kinase-1 in Regulating Survival of Neuroblastoma Cells Exposed to Amyloid-β 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 ␤ (A␤) peptide (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(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; N-acetylcysteine totally abrogated the down-regulation of SphK1 activity and strongly inhibited A␤-induced cell death. SphK1 overexpression impaired the cytotoxicity of A␤, whereas SphK1 silencing by RNA interference mimicked A␤-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 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; 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 A␤-treated cells.

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

“…S1P is known to modulate the secretion of numerous neurotransmitters, growth factors, or hormones [66] and it can also change the cellular levels and secretion of AβPP [67]. SphK overexpression or glycosphingolipid/ceramide depletion inhibits AβPP maturation, its transport, and Aβ toxicity while ceramide stabilizes β-secretase and increases Aβ production [14,15,68]. The matters still seem to be far from clear, as other works show that also S1P can modulate BACE1 [69].…”

RNAi screening in glioma stem-like cells identifies PFKFB4 as a key molecule important for cancer cell survival

“…Statistical significance was calculated using Student's t-test for ranked transformed data. Brain cancer stem-like cells require PFKFB4 for survival V Goidts et al another isozyme of PFK2 that is expressed in normal brain and overexpressed in numerous tumors (Manzano et al, 1998;Kessler and Eschrich, 2001;Atsumi et al, 2002;Gomez-Brouchet et al, 2007). As depicted in Figure 3a, PFKFB3 showed a 1.3-fold higher mean mRNA expression level in primary glioblastomas relative to normal brain tissue and was not overexpressed in the other glioma groups investigated.…”

La sphingosine 1-phosphate comme biomarqueur de la maladie d’Alzheimer ?

“…Cette variation de la concentration en S1P dans certaines régions du cerveau (lobe temporal et hippocampe) était directement liée à une diminution de l'activité des enzymes SphK1 et SphK2 [6]. Parallèlement, nos travaux ont montré une diminution de l'activité de la SphK1 dans des cellules exposées au peptide A (25-35) [13]. Nos travaux plus récents sur des tissus humains ont montré que l'expression de la SphK1 et d'un des récepteurs impli- Le céramide est également métabolisé en sphingosine puis en S1P grâce à l'intervention des sphingosine kinases 1 et 2.…”