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

Lefranc, Florence;Mijatovic, Tatjana;Kondo, Yasuko;Sauvage, Sebastien;Kiss, Robert;et.al.
(2008) Neurosurgery (Baltimore) —

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Authors
  • Lefranc, Florence
    Author
  • Mijatovic, Tatjana
    Author
  • Kondo, Yasuko
    Author
  • Sauvage, Sebastien
    Author
  • Gailly, PhilippeUCLouvain
    Author
  • Kiss, Robert
    Author
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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 alpha 1 subunit, has remained unexplored in GBMs. MATERIALS AND METHODS: The expression of Na+/K+-ATPase alpha 1 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 alpha 1 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 alpha 1 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. CONCLUSION: Inhibition of the Na+/K+-ATPase alpha 1 subunit in human GBM cells impairs both cell migration and cell proliferation.
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Lefranc, F., Mijatovic, T., Kondo, Y., Sauvage, S., Roland, I., Debeir, O., Krstic, D., Vasic, V., Gailly, P., Kondo, S., Blanco, G., & Kiss, R. (2008). Targeting the alpha 1 subunit of the sodium pump to combat glioblastoma cells. Neurosurgery (Baltimore). https://doi.org/10.1227/01.NEU.0000311080.43024.0E