title: A monoclonal antibody against KCNK9 K(+) channel extracellular domain inhibits tumour growth and metastasis.
abstract: Two-pore domain potassium (K2P) channels act to maintain cell resting membrane potential--a prerequisite for many biological processes. KCNK9, a member of K2P family, is implicated in cancer, owing to its overexpression in human tumours and its ability to promote neoplastic cell survival and growth. However, KCNK9's underlying contributions to malignancy remain elusive due to the absence of specific modulators. Here we describe the development of monoclonal antibodies against the KCNK9 extracellular domain and their functional effects. We show that one antibody (Y4) with the highest affinity binding induces channel internalization. The addition of Y4 to KCNK9-expressing carcinoma cells reduces cell viability and increases cell death. Systemic administration of Y4 effectively inhibits growth of human lung cancer xenografts and murine breast cancer metastasis in mice. Evidence for Y4-mediated carcinoma cell autonomous and immune-dependent cytotoxicity is presented. Our study reveals that antibody-based KCNK9 targeting is a promising therapeutic strategy in KCNK9-expressing malignancies.
authors: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205, USA.
authors: Han
authors: H
authors: Sun
authors: Immunotherapy Institute, Fujian Medical University, Fujian 350108, China.
authors: Liqun
authors: L
authors: Luo
authors: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205, USA.
authors: Bachchu
authors: B
authors: Lal
authors: Department of Pathology, University of Maryland, Baltimore, Maryland 21201, USA.
authors: Xinrong
authors: X
authors: Ma
authors: Department of Immunobiology and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06511, USA.
authors: Lieping
authors: L
authors: Chen
authors: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: Christine L
authors: CL
authors: Hann
authors: Department of Pathology, University of Maryland, Baltimore, Maryland 21201, USA.|Baltimore Veterans Administration Medical Center, Baltimore, Maryland 21201, USA.
authors: Amy M
authors: AM
authors: Fulton
authors: Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: Daniel J
authors: DJ
authors: Leahy
authors: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, Maryland 21205, USA.|Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: John
authors: J
authors: Laterra
authors: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors: Min
authors: M
authors: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D019556:COS Cells; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C498655:KCNK9 protein, human; D024683:Potassium Channels, Tandem Pore Domain