• Neurosurgery · Jan 2008

    Targeting the alpha 1 subunit of the sodium pump to combat glioblastoma cells.

    • Florence Lefranc, Tatjana Mijatovic, Yasuko Kondo, Sébastien Sauvage, Isabelle Roland, Olivier Debeir, Danijela Krstic, Vesna Vasic, Philippe Gailly, Seiji Kondo, Gustavo Blanco, and Robert Kiss.
    • Department of Neurosurgery, Erasme Hospital, Free University of Brussels, Route de Lennik, 808, 1070 Brussels, Belgium. fllefran@ulb.ac.be
    • Neurosurgery. 2008 Jan 1; 62 (1): 211-21; discussion 221-2.

    ObjectiveIon 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.Materials And MethodsThe 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.ResultsOverall, 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.ConclusionInhibition of the Na+/K+ -ATPase alpha1 subunit in human GBM cells impairs both cell migration and cell proliferation.

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