title: Expression of S1P metabolizing enzymes and receptors correlate with survival time and regulate cell migration in glioblastoma multiforme.
abstract: A signaling molecule which is involved in proliferation and migration of malignant cells is the lipid mediator sphingosine-1-phosphate (S1P). There are hints for a potential role of S1P signaling in malignant brain tumors such as glioblastoma multiforme (GBM) which is characterized by a poor prognosis. Therefore, a comprehensive expression analysis of S1P receptors (S1P1-S1P5) and S1P metabolizing enzymes in human GBM (n = 117) compared to healthy brain (n = 10) was performed to evaluate their role for patient´s survival. Furthermore, influence of S1P receptor inhibition on proliferation and migration were studied in LN18 GBM cells. Compared to control brain, mRNA levels of S1P1, S1P2, S1P3 and S1P generating sphingosine kinase-1 were elevated in GBM. Kaplan-Meier analyses demonstrated an association between S1P1 and S1P2 with patient´s survival times. In vitro, an inhibitory effect of the SphK inhibitor SKI-II on viability of LN18 cells was shown. S1P itself had no effect on viability but stimulated LN18 migration which was blocked by inhibition of S1P1 and S1P2. The participation of S1P1 and S1P2 in LN18 migration was further supported by siRNA-mediated silencing of these receptors. Immunoblots and inhibition experiments suggest an involvement of the PI3-kinase/AKT1 pathway in the chemotactic effect of S1P in LN18 cells.In summary, our data argue for a role of S1P signaling in proliferation and migration of GBM cells. Individual components of the S1P pathway represent prognostic factors for patients with GBM. Perspectively, a selective modulation of S1P receptor subtypes could represent a therapeutic approach for GBM patients and requires further evaluation.
authors.affiliation: Department of Pharmacology, University Medicine Greifswald, Greifswald, Germany.|Department of Neurosurgery, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Bien-Möller
authors.affiliation: Department of Pharmacology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lange
authors.affiliation: Department of Pharmacology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Holm
authors.affiliation: Department of Pharmacology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Böhm
authors.affiliation: Department of Pharmacology, University Medicine Greifswald, Greifswald, Germany.|Department of Neurosurgery, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Paland
authors.affiliation: Department of Pharmacology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Küpper
authors.affiliation: Department of Pharmacology, University Medicine Greifswald, Greifswald, Germany.|Department of Neurosurgery, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Susann
authors.initials: S
authors.lastname: Herzog
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Weitmann
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Havemann
authors.affiliation: Institute of Pathology, Department of Neuropathology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Vogelgesang
authors.affiliation: Department of Neurosurgery, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Marx
authors.affiliation: Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hoffmann
authors.affiliation: Department of Neurosurgery, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Henry W S
authors.initials: HW
authors.lastname: Schroeder
authors.affiliation: Department of Pharmacology, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Bernhard H
authors.initials: BH
authors.lastname: Rauch
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008246:Lysophospholipids / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D014408:Biomarkers, Tumor; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: S1P receptor signaling; glioblastoma multiforme; sphingosine-1-phosphate