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.

中文翻译：

---

针对KCNK9 K（+）通道胞外域的单克隆抗体抑制肿瘤的生长和转移。

两孔结构域钾（K2P）通道可维持细胞静息膜电位-许多生物学过程的先决条件。KCNK9是K2P家族的成员，由于其在人肿瘤中的过度表达及其促进肿瘤细胞存活和生长的能力，与癌症有关。然而，由于缺乏特定的调节剂，KCNK9对恶性肿瘤的潜在作用仍然难以捉摸。在这里，我们描述了针对KCNK9细胞外域的单克隆抗体的发展及其功能作用。我们显示一种具有最高亲和力结合的抗体（Y4）诱导通道内在化。在表达KCNK9的癌细胞中添加Y4会降低细胞活力并增加细胞死亡。Y4的全身给药有效抑制了人肺癌异种移植物的生长和小鼠的小鼠乳腺癌转移。提出了Y4介导的癌细胞自主性和免疫依赖性细胞毒性的证据。我们的研究表明，基于抗体的KCNK9靶向是表达KCNK9的恶性肿瘤中一种有希望的治疗策略。