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Molecular Pharmacology

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Research ArticleArticle

Critical Role for Sphingosine Kinase-1 in Regulating Survival of Neuroblastoma Cells Exposed to Amyloid-β Peptide

Anne Gomez-Brouchet, Dimitri Pchejetski, Leyre Brizuela, Virginie Garcia, Marie-Françoise Altié, Marie-Lise Maddelein, Marie-Bernadette Delisle and Olivier Cuvillier
Molecular Pharmacology August 2007, 72 (2) 341-349; DOI: https://doi.org/10.1124/mol.106.033738
Anne Gomez-Brouchet
Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France (A.G.-B., D.P., V.G., M.-F.A., M.-B.D., O.C.); Université Toulouse III Paul Sabatier, Toulouse, France (A.G.-B., D.P., L.B., V.G., M.-F.A., M.-L.M., M.-B.D., O.C.); Centre Hospitalier Universitaire Toulouse, Service d'Anatomie et de Cytologie Pathologiques, Toulouse, France (A.G.-B., M.-B.D.); and Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France (D.P., L.B., M.-L.M., O.C.)
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Dimitri Pchejetski
Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France (A.G.-B., D.P., V.G., M.-F.A., M.-B.D., O.C.); Université Toulouse III Paul Sabatier, Toulouse, France (A.G.-B., D.P., L.B., V.G., M.-F.A., M.-L.M., M.-B.D., O.C.); Centre Hospitalier Universitaire Toulouse, Service d'Anatomie et de Cytologie Pathologiques, Toulouse, France (A.G.-B., M.-B.D.); and Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France (D.P., L.B., M.-L.M., O.C.)
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Leyre Brizuela
Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France (A.G.-B., D.P., V.G., M.-F.A., M.-B.D., O.C.); Université Toulouse III Paul Sabatier, Toulouse, France (A.G.-B., D.P., L.B., V.G., M.-F.A., M.-L.M., M.-B.D., O.C.); Centre Hospitalier Universitaire Toulouse, Service d'Anatomie et de Cytologie Pathologiques, Toulouse, France (A.G.-B., M.-B.D.); and Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France (D.P., L.B., M.-L.M., O.C.)
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Virginie Garcia
Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France (A.G.-B., D.P., V.G., M.-F.A., M.-B.D., O.C.); Université Toulouse III Paul Sabatier, Toulouse, France (A.G.-B., D.P., L.B., V.G., M.-F.A., M.-L.M., M.-B.D., O.C.); Centre Hospitalier Universitaire Toulouse, Service d'Anatomie et de Cytologie Pathologiques, Toulouse, France (A.G.-B., M.-B.D.); and Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France (D.P., L.B., M.-L.M., O.C.)
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Marie-Françoise Altié
Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France (A.G.-B., D.P., V.G., M.-F.A., M.-B.D., O.C.); Université Toulouse III Paul Sabatier, Toulouse, France (A.G.-B., D.P., L.B., V.G., M.-F.A., M.-L.M., M.-B.D., O.C.); Centre Hospitalier Universitaire Toulouse, Service d'Anatomie et de Cytologie Pathologiques, Toulouse, France (A.G.-B., M.-B.D.); and Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France (D.P., L.B., M.-L.M., O.C.)
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Marie-Lise Maddelein
Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France (A.G.-B., D.P., V.G., M.-F.A., M.-B.D., O.C.); Université Toulouse III Paul Sabatier, Toulouse, France (A.G.-B., D.P., L.B., V.G., M.-F.A., M.-L.M., M.-B.D., O.C.); Centre Hospitalier Universitaire Toulouse, Service d'Anatomie et de Cytologie Pathologiques, Toulouse, France (A.G.-B., M.-B.D.); and Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France (D.P., L.B., M.-L.M., O.C.)
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Marie-Bernadette Delisle
Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France (A.G.-B., D.P., V.G., M.-F.A., M.-B.D., O.C.); Université Toulouse III Paul Sabatier, Toulouse, France (A.G.-B., D.P., L.B., V.G., M.-F.A., M.-L.M., M.-B.D., O.C.); Centre Hospitalier Universitaire Toulouse, Service d'Anatomie et de Cytologie Pathologiques, Toulouse, France (A.G.-B., M.-B.D.); and Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France (D.P., L.B., M.-L.M., O.C.)
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Olivier Cuvillier
Institut National de la Santé et de la Recherche Médicale U466, Toulouse, France (A.G.-B., D.P., V.G., M.-F.A., M.-B.D., O.C.); Université Toulouse III Paul Sabatier, Toulouse, France (A.G.-B., D.P., L.B., V.G., M.-F.A., M.-L.M., M.-B.D., O.C.); Centre Hospitalier Universitaire Toulouse, Service d'Anatomie et de Cytologie Pathologiques, Toulouse, France (A.G.-B., M.-B.D.); and Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, Unité Mixte de Recherche 5089, Toulouse, France (D.P., L.B., M.-L.M., O.C.)
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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 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.

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Molecular Pharmacology: 72 (2)
Molecular Pharmacology
Vol. 72, Issue 2
1 Aug 2007
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Research ArticleArticle

Critical Role for Sphingosine Kinase-1 in Regulating Survival of Neuroblastoma Cells Exposed to Amyloid-β Peptide

Anne Gomez-Brouchet, Dimitri Pchejetski, Leyre Brizuela, Virginie Garcia, Marie-Françoise Altié, Marie-Lise Maddelein, Marie-Bernadette Delisle and Olivier Cuvillier
Molecular Pharmacology August 1, 2007, 72 (2) 341-349; DOI: https://doi.org/10.1124/mol.106.033738

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Research ArticleArticle

Critical Role for Sphingosine Kinase-1 in Regulating Survival of Neuroblastoma Cells Exposed to Amyloid-β Peptide

Anne Gomez-Brouchet, Dimitri Pchejetski, Leyre Brizuela, Virginie Garcia, Marie-Françoise Altié, Marie-Lise Maddelein, Marie-Bernadette Delisle and Olivier Cuvillier
Molecular Pharmacology August 1, 2007, 72 (2) 341-349; DOI: https://doi.org/10.1124/mol.106.033738
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