biostudies-literatureSun HNIMH NIH HHSNCI NIH HHSNINDS NIH HHSNIGMS NIH HHS10339https://www.ebi.ac.uk/biostudies/studies/S-EPMC4742836biostudies-literatureUnknown7Two-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.Nature communicationsA monoclonal antibody against KCNK9 K(+) channel extracellular domain inhibits tumour growth and metastasis.PMC4742836GM078579R01 NS073611NS050274U54 MH084691NS073611R01 GM078579MH084691P30 CA016359P30 NS050274Lal BLuo LChen LHann CLFulton AMMa XLeahy DJSun HLi MLaterra JfalseA monoclonal antibody against KCNK9 K(+) channel extracellular domain inhibits tumour growth and metastasis.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.2016-01-01T00:00:00Z2016 Feb2024-12-04T00:46:33.095Z2019-03-27T02:08:32ZS-EPMC47428362684234210.1038/ncomms10339