Matrine is a novel inhibitor of the TMEM16A chloride channel with antilung adenocarcinoma effects

Calcium‐activated chloride channels (CaCCs) are ion channels with key roles in physiological processes. They are abnormally expressed in various cancers, including esophageal squamous cell cancer, head and neck squamous cell carcinoma, colorectal cancer, and gastrointestinal stromal tumors. The CaCC...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of cellular physiology 2019-06, Vol.234 (6), p.8698-8708
Hauptverfasser: Guo, Shuai, Chen, Yafei, Pang, Chunli, Wang, Xuzhao, Shi, Sai, Zhang, Hailin, An, Hailong, Zhan, Yong
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Calcium‐activated chloride channels (CaCCs) are ion channels with key roles in physiological processes. They are abnormally expressed in various cancers, including esophageal squamous cell cancer, head and neck squamous cell carcinoma, colorectal cancer, and gastrointestinal stromal tumors. The CaCC component TMEM16A/ANO1 was recently shown to be overexpressed in lung adenocarcinoma cells and may serve as a tumorigenic protein. In this study, we determined that matrine is a potent TMEM16A inhibitor that exerts anti‐lung adenocarcinoma effects. Patch clamp experiments showed that matrine inhibited TMEM16A current in a concentration‐dependent manner with an IC 50 of 27.94 ± 4.78 μM. Molecular simulation and site‐directed mutation experiments demonstrated that the matrine‐sensitive sites of the TMEM16A channel involve the amino acids Y355, F411, and F415. Results of cell viability and wound healing assays showed that matrine significantly inhibited the proliferation and migration of LA795 cells, which exhibit high TMEM16A expression. In contrast, matrine has only weak inhibitory effect on CCD‐19Lu and HeLa cells lacking TMEM16A expression. Matrine‐induced effects on the proliferation and migration of LA795 cells were abrogated upon shRNA‐mediated TMEM16A knockdown in LA795 cells. Finally, in vivo experiments demonstrated that matrine dramatically inhibited the growth of lung adenocarcinoma xenograft tumors in mice but did not affect mouse body weight. Collectively, these data indicate that matrine is an effective and safe TMEM16A inhibitor and that TMEM16A is the target of matrine anti‐lung adenocarcinoma activity. These findings provide new insight for the development of novel treatments for lung adenocarcinoma. We find matrine is a natural product inhibitor of TMEM16A and explored its inhibitory effects on lung adenocarcinoma in vitro and in vivo. We identified the putative matrine‐sensitive sites of the TMEM16A ion channel. Our findings shed light on the future development of novel treatments for lung adenocarcinoma.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.27529