Abstract
The expression levels of anoctamin 1 (ANO1, TMEM16A), a calcium-activated chloride channel (CaCC), are significantly increased in several tumors, and inhibition of ANO1 is known to reduce cell proliferation and migration. Here, we performed cell-based screening of a collection of natural products and drug-like compounds to identify inhibitors of ANO1. As a result of the screening, idebenone, miconazole and plumbagin were identified as novel ANO1 inhibitors. Electrophysiological studies showed that idebenone, a synthetic analog of coenzyme Q10, completely blocked ANO1 activity in FRT cells expressing ANO1 without any effect on intracellular calcium signaling and CFTR, a cAMP-regulated chloride channel. The CaCC activities in PC-3 and CFPAC-1 cells expressing abundant endogenous ANO1 were strongly blocked by idebenone. Idebenone inhibited cell proliferation and induced apoptosis in PC-3 and CFPAC-1 cells, but not in A549 cells, which do not express ANO1. These data suggest that idebenone, a novel ANO1 inhibitor, has potential for use in cancer therapy.
Highlights
Calcium-activated Cl- channels (CaCCs) are widely expressed in various cell types and tissues, and they are implicated in many physiological activities such as epithelial fluid secretion, smooth muscle contraction, and sensory signal transduction [1,2,3]
In 2008, three independent research groups reported that anoctamin-1 (ANO1, TMEM16A) gene encodes a CaCC, showing calcium-activated Cl- currents when it was expressed in oocytes and mammalian cells [5,6,7]
Several studies have indicated that ANO1 may be used as a therapeutic target of tumors because down regulation of ANO1 showed potential therapeutic benefits on head-and-neck squamous cell carcinoma (HNSCC), esophageal squamous cell carcinoma (ESCC), gastrointestinal stromal tumours (GIST), breast and prostate cancer [14, 16, 30, 32, 33]
Summary
Calcium-activated Cl- channels (CaCCs) are widely expressed in various cell types and tissues, and they are implicated in many physiological activities such as epithelial fluid secretion, smooth muscle contraction, and sensory signal transduction [1,2,3]. CaCCs were first described over 3 decades ago but the molecular identity of CaCCs has recently been identified [4]. In 2008, three independent research groups reported that anoctamin-1 (ANO1, TMEM16A) gene encodes a CaCC, showing calcium-activated Cl- currents when it was expressed in oocytes and mammalian cells [5,6,7]. ANO1 is expressed in various cell types including tracheal, intestinal, and glandular epithelia, smooth muscle cells, intestinal pacemaker cells, sensory neurons, and several tumors [5, 7,8,9].
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