title: Inhibition of sphingosine kinase 1 suppresses proliferation of glioma cells under hypoxia by attenuating activity of extracellular signal-regulated kinase.
abstract: OBJECTIVE
  Sphingosine kinase (SphK), which is regulated by hypoxia, catalyses phosphorylation of sphingosine to produce sphingosine-1-phosphate, which stimulates invasiveness of gliomas. However, whether SphK is involved in proliferation of glioma cells under hypoxic conditions is not clearly understood. In this study, we have investigated the role of SphK in of proliferation glioma cells under hypoxia.
  
  
  METHODS
  Effects of small interfering RNA (siRNA) on SphKs, SKI (inhibitor of SphK) and U0126 (inhibitor of ERK) on proliferation of glioma cells under hypoxia were studied using CCK-8 assay and flow cytometry. Protein expression profiles were evaluated by Western blot analysis.
  
  
  RESULTS
  SKI suppressed proliferation of glioma cells under hypoxia. Similarly, downregulation of SphKs by siRNA inhibited glioma cell proliferation, and the cell cycle was arrested in G(2) /M phase when SphK1 was inhibited. In addition, inhibition of SphK1 attenuated phosphorylation of ERK in hypoxic conditions. Furthermore, U0126 markedly inhibited cell population growth and arrested cells in G(2) /M as effectively as SKI. However, silencing SphK2 induced cell cycle arrest in the S phase and it showed little effect on hypoxia-induced activation of ERK.
  
  
  CONCLUSIONS
  SphK1 and SphK2 are involved in proliferation of glioma cells in hypoxic conditions through distinct signalling pathways. SphK1, but not SphK2, promotes cell population expansion in hypoxic conditions by activating ERK.
authors.affiliation: Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.forename: S
authors.initials: S
authors.lastname: Yu
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.forename: F
authors.initials: F
authors.lastname: Zou
mesh_terms: D001483:Base Sequence; D002070:Butadienes / Q000494:pharmacology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D009570:Nitriles; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D000099157:Sphingosine Kinase; C113580:U 0126