Abstract
TMEM16A, a calcium-activated chloride channel (CaCC), is highly amplified and expressed in human cancers and is involved in the growth and metastasis of some malignancies. Inhibition of TMEM16A represents a novel pharmaceutical approach for the treatment of cancers and metastases. The purpose of this study is to identify a new TMEM16A inhibitor, investigate the effects of this inhibitor on the proliferation and metastasis of TMEM16A-amplified SW620 cells, and to elucidate the underlying molecular mechanism in vitro. We identified a novel small-molecule TMEM16A inhibitor dehydroandrographolide (DP). By using patch clamp electrophysiology, we showed that DP inhibited TMEM16A chloride currents in Fisher rat thyroid (FRT) cells that were transfected stably with human TMEM16A and in TMEM16A-overexpressed SW620 cells but did not alter cystic fibrosis transmembrane conductance regulator (CFTR) chloride currents. Further functional studies showed that DP suppressed the proliferation of SW620 cells in a dose- and time-dependent manner using MTT assays. Moreover, DP significantly inhibited migration and invasion of SW620 cells as detected by wound-healing and transwell assays. Further mechanistic study demonstrated that knockdown of human TMEM16A decreased the inhibitory effect of DP on the proliferation of SW620 cells and that TMEM16A-dependent cells (SW620 and HCT116) were more sensitive to DP than TMEM16A-independent cells (SW480 and HCT8). In addition, we found that treatment of SW620 cells with DP led to a decrease in TMEM16A protein levels but had no effect on TMEM16A mRNA levels. The current work reveals that DP, a novel TMEM16A inhibitor, exerts its anticancer activity on SW620 cells partly through a TMEM16A-dependent mechanism, which may introduce a new targeting approach for an antitumour therapy in TMEM16A-amplified cancers.
Highlights
Multiple genetic abnormalities take place during the process of transformation of a normal cell into a cancer cell
Transmembrane protein 16A (TMEM16A) is known as ANO1, DOG1, TAOS2, and ORAOV2, because it was known to be amplified and overexpressed in cancers before it was identified as a calcium-activated chloride channel (CaCC) with eight putative transmembrane domains and N- and C-termini oriented towards the cytoplasm [9,10,11]
The effects of DP on TMEM16A-CaCC activity in Fisher rat thyroid (FRT) cells transfected with human TMEM16A
Summary
Multiple genetic abnormalities take place during the process of transformation of a normal cell into a cancer cell. The pharmacologic blockade of ion channels is a promising antitumour therapy. Transmembrane protein 16A (TMEM16A) calcium-activated chloride channels (CaCCs) are amplified and highly expressed in several human cancers, such as head and neck squamous carcinoma (HNSCC), breast cancer, oesophageal squamous carcinoma (ESSC), gastrointestinal stromal tumours and prostate cancer [2,3,4,5,6,7,8]. Down-regulation of TMEM16A protein levels by RNAi and pharmacologic blockade decrease the proliferation of breast cancer, prostate cancer and HNSCC by affecting the activation of the MAPK/AKT signalling pathways [14,17]. TMEM16A regulates the migration and metastasis of some types of cancers [18]. Few TMEM16A inhibitors have been identified, and how TMEM16A inhibitors affect cancer progression and metastasis is unknown
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