41 / 2021-07-28 16:56:15

Inhibitory effect of daidzein on TMEM16A and its anti-lung adenocarcinoma activity

TMEM16A; inhibitor; daidzein; lung adenocarcinoma

TMEM16A is the molecular basis of calcium-activated chloride channels (CaCCs), and it is highly expressed in a variety of tumor cells and is involved in the growth and metastasis of malignancies. The available data showed that down-regulation of TMEM16A expression and functional activity can inhibit tumor cells proliferation and migration. According to cancer statistics, the incidence and mortality of lung cancer are at the forefront of all types of cancer. However, there is a lack of targeted inhibitors with high efficiency and low toxicity. Therefore, the purpose of this work was to identify a new TMEM16A inhibitor and research its effect on lung adenocarcinoma cells. Here, we screened and identified a novel inhibitor daidzein. Whole-cell patch clamp data indicated that daidzein inhibits TMEM16A channel in a dose-dependent manner, with IC50 of 1.39±0.59 μM. Western blot result showed that daidzein can reduce the expression of TMEM16A protein in LA795 cells. The inhibition of TMEM16A current and the down-regulation of TMEM16A protein indicate that daidzein can not only inhibit the function of TMEM16A, but also reduce the expression of TMEM16A, showing a two-way regulation. Through molecular docking, the putative binding sites of daidzein and TMEM16A are G608, G628, and K839. Moreover, the results of in vitro cells and in vivo animal experiments showed that daidzein concentration-dependently reduced cell viability and cell migration, causing G1/S cell cycle arrest. And it was confirmed that daidzein can effectively inhibit the growth of LA795 lung adenocarcinoma cells in nude mice. In conclusion, daidzein can be used as a lead compound for the development of therapeutic drugs for lung adenocarcinoma.