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Nat Neurosci. 2015 Sep;18(9):1236-46. doi: 10.1038/nn.4088. Epub 2015 Aug 10.

EAG2 potassium channel with evolutionarily conserved function as a brain tumor target.

Author information

1
Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.
2
Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
3
Developmental and Stem Cell Program, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
4
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
5
The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
6
Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA.
7
Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
8
Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
9
Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
10
Department of Neurological Surgery and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California USA.
11
Department of Neurology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
12
Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

Abstract

Over 20% of the drugs for treating human diseases target ion channels, but no cancer drug approved by the US Food and Drug Administration (FDA) is intended to target an ion channel. We found that the EAG2 (Ether-a-go-go 2) potassium channel has an evolutionarily conserved function for promoting brain tumor growth and metastasis, delineate downstream pathways, and uncover a mechanism for different potassium channels to functionally cooperate and regulate mitotic cell volume and tumor progression. EAG2 potassium channel was enriched at the trailing edge of migrating medulloblastoma (MB) cells to regulate local cell volume dynamics, thereby facilitating cell motility. We identified the FDA-approved antipsychotic drug thioridazine as an EAG2 channel blocker that reduces xenografted MB growth and metastasis, and present a case report of repurposing thioridazine for treating a human patient. Our findings illustrate the potential of targeting ion channels in cancer treatment.

PMID:
26258683
PMCID:
PMC4639927
DOI:
10.1038/nn.4088
[Indexed for MEDLINE]
Free PMC Article
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