title: EAG2 potassium channel with evolutionarily conserved function as a brain tumor target.
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.
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Huang
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: He
authors.affiliation: Developmental and Stem Cell Program, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Jüri
authors.initials: J
authors.lastname: Reimand
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Huanghe
authors.initials: H
authors.lastname: Yang
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Tongfei A
authors.initials: TA
authors.lastname: Wang
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Stehbens
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Younger
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Barshow
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Sijun
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Cooper
authors.affiliation: Developmental and Stem Cell Program, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Peacock
authors.affiliation: Developmental and Stem Cell Program, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Vijay
authors.identifier: http://orcid.org/0000-0002-6557-895X
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: Developmental and Stem Cell Program, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Livia
authors.initials: L
authors.lastname: Garzia
authors.affiliation: Developmental and Stem Cell Program, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Developmental and Stem Cell Program, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Marc
authors.identifier: http://orcid.org/0000-0002-9404-9993
authors.initials: M
authors.lastname: Remke
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Forester
authors.affiliation: Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.|Department of Neurological Surgery and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California USA.|Department of Neurology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Department of Medicine and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Shuman
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gary D
authors.identifier: http://orcid.org/0000-0003-0185-8861
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Department of Neurology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Sabine
authors.identifier: http://orcid.org/0000-0002-8216-9357
authors.initials: S
authors.lastname: Mueller
authors.affiliation: Developmental and Stem Cell Program, Arthur and Sonia Labatt Brain Tumor Research Centre, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Yuh Nung
authors.initials: YN
authors.lastname: Jan
authors.affiliation: Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco, San Francisco, California, USA.|Howard Hughes Medical Institute, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Lily Yeh
authors.initials: LY
authors.lastname: Jan
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004330:Drosophila; D016503:Drug Delivery Systems / Q000379:methods*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D013881:Thioridazine / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D055815:Young Adult
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; C485729:KCNH5 protein, human; D013881:Thioridazine