Seo Yohan, Ryu Kunhi, Park Jinhong, Jeon Dong-Kyu, Jo Sungwoo, Lee Ho K, Namkung Wan
College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea.
Department of Integrated OMICS for Biomedical Science, WCU Program of Graduate School, Yonsei University, Seoul, Korea.
PLoS One. 2017 Mar 31;12(3):e0174935. doi: 10.1371/journal.pone.0174935. eCollection 2017.
Anoctamin 1 (ANO1), a calcium-activated chloride channel, is highly amplified in prostate cancer, the most common form of cancer and leading causes of cancer death in men, and downregulation of ANO1 expression or its functional activity is known to inhibit cell proliferation, migration and invasion in prostate cancer cells. Here, we performed a cell-based screening for the identification of ANO1 inhibitors as potential anticancer therapeutic agents for prostate cancer. Screening of ~300 selected bioactive natural products revealed that luteolin is a novel potent inhibitor of ANO1. Electrophysiological studies indicated that luteolin potently inhibited ANO1 chloride channel activity in a dose-dependent manner with an IC50 value of 9.8 μM and luteolin did not alter intracellular calcium signaling in PC-3 prostate cancer cells. Luteolin inhibited cell proliferation and migration of PC-3 cells expressing high levels of ANO1 more potently than that of ANO1-deficient PC-3 cells. Notably, luteolin not only inhibited ANO1 channel activity, but also strongly decreased protein expression levels of ANO1. Our results suggest that downregulation of ANO1 by luteolin is a potential mechanism for the anticancer effect of luteolin.
anoctamin 1（ANO1）是一种钙激活氯离子通道，在前列腺癌中高度扩增，前列腺癌是男性最常见的癌症形式和癌症死亡的主要原因，已知下调ANO1表达或其功能活性可抑制前列腺癌细胞的增殖、迁移和侵袭。在此，我们进行了基于细胞的筛选，以鉴定ANO1抑制剂作为前列腺癌的潜在抗癌治疗药物。对约300种选定的生物活性天然产物进行筛选后发现，木犀草素是一种新型的强效ANO1抑制剂。电生理研究表明，木犀草素以剂量依赖性方式有效抑制ANO1氯离子通道活性，IC50值为9.8 μM，且木犀草素不会改变PC-3前列腺癌细胞中的细胞内钙信号传导。与ANO1缺陷的PC-3细胞相比，木犀草素更有效地抑制了高表达ANO1的PC-3细胞的增殖和迁移。值得注意的是，木犀草素不仅抑制ANO1通道活性，还强烈降低ANO1的蛋白表达水平。我们的结果表明，木犀草素下调ANO1是其抗癌作用的潜在机制。
