Targeting the alpha 1 subunit of the sodium pump to combat glioblastoma cells.
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.
Lefranc
Florence
F
Department of Neurosurgery, Erasme Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium. fllefran@ulb.ac.be
Mijatovic
Tatjana
T
Kondo
Yasuko
Y
Sauvage
Sébastien
S
Roland
Isabelle
I
Debeir
Olivier
O
Krstic
Danijela
D
Vasic
Vesna
V
Gailly
Philippe
P
Kondo
Seiji
S
Blanco
Gustavo
G
Kiss
Robert
R
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
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