Document Detail


Inhibition of transient receptor potential canonical channels impairs cytokinesis in human malignant gliomas.
MedLine Citation:
PMID:  18211288     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: Glial-derived primary brain tumours, gliomas, are among the fastest growing malignancies and present a huge clinical challenge. Research suggests an important, yet poorly understood, role of ion channels in growth control of normal and malignant cells. In this study, we sought to functionally characterize Transient Receptor Potential Canoncial (TRPC) channels in glioma cell proliferation. TRPC channels form non-selective cation channels that have been suggested to represent a Ca(2+) influx pathway impacting cellular growth.
MATERIALS AND METHODS: Employing a combination of molecular, biochemical and biophysical techniques, we characterized TRPC channels in glioma cells.
RESULTS: We showed consistent expression of four channel family members (TRPC-1, -3, -5, -6) in glioma cell lines and acute patient-derived tissues. These channels gave rise to small, non-voltage-dependent cation currents that were blocked by the TRPC inhibitors GdCl(3), 2-APB, or SKF96365. Importantly, TRPC channels contributed to the resting conductance of glioma cells and their acute pharmacological inhibition caused an approximately 10 mV hyperpolarization of the cells' resting potential. Additionally, chronic application of the TRPC inhibitor SKF96365 caused near complete growth arrest. A detailed analysis, by fluorescence-activated cell sorting and time-lapse microscopy, showed that growth inhibition occurred at the G(2)+ M phase of the cell cycle with cytokinesis defects. Cells underwent incomplete cell divisions and became multinucleate, enlarged cells.
CONCLUSIONS: Nuclear atypia and enlarged cells are histopathological hallmarks for glioblastoma multiforme, the highest grade glioma, suggesting that a defect in TRPC channel function may contribute to cellular abnormalities in these tumours.
Authors:
V C Bomben; H W Sontheimer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Cell proliferation     Volume:  41     ISSN:  1365-2184     ISO Abbreviation:  Cell Prolif.     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-01-23     Completed Date:  2008-03-31     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  9105195     Medline TA:  Cell Prolif     Country:  England    
Other Details:
Languages:  eng     Pagination:  98-121     Citation Subset:  IM    
Affiliation:
Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, AL 35294, USA.
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MeSH Terms
Descriptor/Qualifier:
Biopsy
Blotting, Western
Boron Compounds / pharmacology
Brain Neoplasms / metabolism,  pathology*
Cell Cycle*
Cell Line, Tumor
Cell Proliferation
Glioma / metabolism,  pathology*
Humans
Imidazoles / pharmacology
Immunohistochemistry
Transient Receptor Potential Channels / antagonists & inhibitors*,  metabolism,  physiology
Grant Support
ID/Acronym/Agency:
R01 NS-31234/NS/NINDS NIH HHS; R01 NS-36692/NS/NINDS NIH HHS; R01 NS031234-14A1/NS/NINDS NIH HHS; R01 NS031234-15/NS/NINDS NIH HHS; R01 NS036692-08/NS/NINDS NIH HHS; R01 NS036692-09A2/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/2-aminoethoxydiphenylborane; 0/Boron Compounds; 0/Imidazoles; 0/Transient Receptor Potential Channels; 130495-35-1/1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
Comments/Corrections

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