Document Detail


Inhibition of the Sodium-Potassium-Chloride Cotransporter Isoform-1 reduces glioma invasion.
MedLine Citation:
PMID:  20570904     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Brian R Haas; Harald Sontheimer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-06-22
Journal Detail:
Title:  Cancer research     Volume:  70     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-02     Completed Date:  2010-08-09     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5597-606     Citation Subset:  IM    
Copyright Information:
Copyright 2010 AACR.
Affiliation:
Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain Neoplasms / drug therapy*,  metabolism*,  pathology
Bumetanide / pharmacology*
Cell Line, Tumor
Cell Movement / drug effects,  genetics
Female
Gene Knockdown Techniques
Glioma / drug therapy*,  metabolism*,  pathology
Humans
Mice
Mice, SCID
Neoplasm Invasiveness
RNA, Small Interfering / genetics
Sodium Potassium Chloride Symporter Inhibitors / pharmacology*
Sodium-Potassium-Chloride Symporters / genetics,  metabolism*
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
NS57098/NS/NINDS NIH HHS; P30 HD038985/HD/NICHD NIH HHS; P30 HD038985-08/HD/NICHD NIH HHS; P30 NS057098-05/NS/NINDS NIH HHS; R01 NS031234-18/NS/NINDS NIH HHS; R01 NS036692-12/NS/NINDS NIH HHS; R01-031234//PHS HHS; R01-036692//PHS HHS
Chemical
Reg. No./Substance:
0/RNA, Small Interfering; 0/Sodium Potassium Chloride Symporter Inhibitors; 0/Sodium-Potassium-Chloride Symporters; 0/sodium-potassium-chloride cotransporter 1 protein; 28395-03-1/Bumetanide
Comments/Corrections

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