Inhibition of the Sodium-Potassium-Chloride Cotransporter Isoform-1 Reduces Glioma Invasion
- 30 June 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 70 (13), 5597-5606
- https://doi.org/10.1158/0008-5472.can-09-4666
Abstract
Malignant gliomas metastasize throughout the brain by infiltrative cell migration into peritumoral areas. Invading cells undergo profound changes in cell shape and volume as they navigate extracellular spaces along blood vessels and white matter tracts. Volume changes are aided by the concerted release of osmotically active ions, most notably K+ and Cl−. Their efflux through ion channels along with obligated water causes rapid cell shrinkage. Suitable ionic gradients must be established and maintained through the activity of ion transport systems. Here, we show that the Sodium-Potassium-Chloride Cotransporter Isoform-1 (NKCC1) provides the major pathway for Cl− accumulation in glioma cells. NKCC1 localizes to the leading edge of invading processes, and pharmacologic inhibition using the loop diuretic bumetanide inhibits in vitro Transwell migration by 25% to 50%. Short hairpin RNA knockdowns of NKCC1 yielded a similar inhibition and a loss of bumetanide-sensitive cell volume regulation. A loss of NKCC1 function did not affect cell motility in two-dimensional assays lacking spatial constraints but manifested only when cells had to undergo volume changes during migration. Intracranial implantation of human gliomas into severe combined immunodeficient mice showed a marked reduction in cell invasion when NKCC1 function was disrupted genetically or by twice daily injection of the Food and Drug Administration–approved NKCC1 inhibitor Bumex. These data support the consideration of Bumex as adjuvant therapy for patients with high-grade gliomas. Cancer Res; 70(13); 5597–606. ©2010 AACR.Keywords
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This publication has 44 references indexed in Scilit:
- Molecular Interaction and Functional Regulation of ClC-3 by Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) in Human Malignant GliomaJournal of Biological Chemistry, 2010
- Functional coupling of apical Cl−/HCO3− exchange with CFTR in stimulated HCO3− secretion by guinea pig interlobular pancreatic ductAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2009
- Chloride Accumulation Drives Volume Dynamics Underlying Cell Proliferation and MigrationJournal of Neurophysiology, 2009
- Chloride Is Essential for Capacitation and for the Capacitation-associated Increase in Tyrosine PhosphorylationJournal of Biological Chemistry, 2008
- ClC3 Is a Critical Regulator of the Cell Cycle in Normal and Malignant Glial CellsJournal of Neuroscience, 2008
- An Unexpected Role for Ion Channels in Brain Tumor MetastasisExperimental Biology and Medicine, 2008
- Inhibition of transient receptor potential canonical channels impairs cytokinesis in human malignant gliomasCell Proliferation, 2008
- Autocrine Glutamate Signaling Promotes Glioma Cell InvasionCancer Research, 2007
- Differential Distribution of Kir4.1 in Spinal Cord Astrocytes Suggests Regional Differences in K+ HomeostasisJournal of Neurophysiology, 2007
- Extracellular glutamine is a critical modulator for regulatory volume increase in human glioma cellsBrain Research, 2007