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.

MATERIALS AND 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.

CONCLUSION:

Inhibition of the Na+/K+ -ATPase alpha1 subunit in human GBM cells impairs both cell migration and cell proliferation.

• Authors: Florence Lefranc, Tatjana Mijatovic, Yasuko Kondo, Sébastien Sauvage, Isabelle Roland, Olivier Debeir, Danijela Krstic, Vesna Vasic, Philippe Gailly, Seiji Kondo, Gustavo Blanco, Robert Kiss
• Journal: Neurosurgery (Neurosurgery) Vol. 62 Issue 1 Pg. 211-21; discussion 221-2 (Jan 2008) ISSN: 1524-4040 [Electronic] United States
• PMID: 18300910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Beclin-1
• Becn1 protein, mouse
• Cardenolides
• Proteins
• Tetrazolium Salts
• Thiazoles
• UNBS 1450
• Green Fluorescent Proteins
• Adenosine Triphosphate
• Sodium-Potassium-Exchanging ATPase
• thiazolyl blue
• Calcium

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Apoptosis Regulatory Proteins
• Beclin-1
• Brain
• Calcium (metabolism)
• Cardenolides (pharmacology, therapeutic use)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Glioblastoma (drug therapy, pathology)
• Green Fluorescent Proteins (biosynthesis)
• Humans
• Mice
• Mice, Nude
• Neoplasm Transplantation (methods)
• Neoplasms, Experimental (drug therapy)
• Proteins (metabolism)
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors, metabolism)
• Statistics, Nonparametric
• Tetrazolium Salts
• Thiazoles
• Transfection