title: Targeting the alpha 1 subunit of the sodium pump to combat glioblastoma cells.
abstract: OBJECTIVE
  Ion transporters play pivotal roles in cancer cell migration in general and in glioblastomas (GBMs) in particular. However, the specific role of Na/K-ATPase (the sodium pump) and, in particular, its alpha1 subunit, has remained unexplored in GBMs.
  
  
  METHODS
  The expression of Na+/K+ -ATPase alpha1 in GBM clinical samples, normal brain tissue, and a human GBM cell line has been investigated. Using the novel cardenolide UNBS1450 (Unibioscreen, Brussels, Belgium), which is a ligand of the sodium pump, we have characterized the effects of inhibiting Na+/K+ -ATPase alpha1 in human GBM cells with respect to cell proliferation; morphology; impact on intracellular Na+, Ca2+, and adenosine triphosphate; and changes in the actin cytoskeleton. We have investigated the mechanism by which UNBS1450 overcomes the apoptosis resistance of GBMs and determined its anti-tumor effects in comparative studies in vitro in GBM cell viability assays and in vivo using an orthotopic human GBM xenograft model.
  
  
  RESULTS
  Overall, the alpha1 subunit of Na+/K+ -ATPase is highly expressed in a majority of glioblastomas compared with normal brain tissues, and by binding to this subunit in human U373-MG GBM cells, UNBS1450 impairs cell proliferation and migration via an intracellular adenosine triphosphate decrease-mediated disorganization of the actin cytoskeleton and cytotoxic proautophagic effects. UNBS1450 also significantly increases the in vivo survival of mice orthotopically grafted with U373-MG GBM cells.
  
  
  CONCLUSIONS
  Inhibition of the Na+/K+ -ATPase alpha1 subunit in human GBM cells impairs both cell migration and cell proliferation.
authors.affiliation: Department of Neurosurgery, Erasme Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium. fllefran@ulb.ac.be
authors.forename: Florence
authors.initials: F
authors.lastname: Lefranc
authors.forename: Tatjana
authors.initials: T
authors.lastname: Mijatovic
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kondo
authors.forename: Sébastien
authors.initials: S
authors.lastname: Sauvage
authors.forename: Isabelle
authors.initials: I
authors.lastname: Roland
authors.forename: Olivier
authors.initials: O
authors.lastname: Debeir
authors.forename: Danijela
authors.initials: D
authors.lastname: Krstic
authors.forename: Vesna
authors.initials: V
authors.lastname: Vasic
authors.forename: Philippe
authors.initials: P
authors.lastname: Gailly
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
authors.forename: Gustavo
authors.initials: G
authors.lastname: Blanco
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D001921:Brain; D002118:Calcium / Q000378:metabolism; D002298:Cardenolides / Q000494:pharmacology* / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011506:Proteins / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D002298:Cardenolides; D011506:Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; C510008:UNBS 1450; D049452:Green Fluorescent Proteins; D000255:Adenosine Triphosphate; D000254:Sodium-Potassium-Exchanging ATPase; C022616:thiazolyl blue; D002118:Calcium