Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation.
Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation.
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DOI：
10.1111/cas.15079
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发表时间：
2021-10
期刊：
影响因子：
5.7
通讯作者：
Suzuki A
中科院分区：
文献类型：
--
作者：
Nakatani K;Maehama T;Nishio M;Otani J;Yamaguchi K;Fukumoto M;Hikasa H;Hagiwara S;Nishina H;Mak TW;Honma T;Kondoh Y;Osada H;Yoshida M;Suzuki A
是相关蛋白1（YAP 1）及其旁PDZ结合基序（TAZ）在细胞增殖，迁移和侵袭中起着关键作用，这些TEAD转录辅激活因子的异常激活在人类和小鼠的多种癌症中被发现。因此，靶向YAP 1/TAZ信号传导是一种有前途的治疗途径，但迄今为止，很少有选择性YAP 1/TAZ抑制剂在体外或体内对癌细胞有效。我们使用高度灵敏的荧光素酶报告系统筛选有效的YAP 1/TAZ抑制剂的化学文库，以监测细胞中的YAP 1/TAZ-TEAD转录活性。在筛选的29049种低分子量化合物中，我们获得了9个命中，其中4个最有效的与天然产物土兰内酯（ALT）共享核心结构。我们还测试了ALT的其他16种结构衍生物，发现天然ALT在增加ROS诱导的LATS激酶活性和YAP 1/TAZ磷酸化方面最有效。磷酸化的YAP 1/TAZ蛋白受到核排斥和蛋白质体降解，使得ALT处理的肿瘤细胞的生长在体外和体内都受到抑制。我们的数据首次表明ALT可用于靶向驱动肿瘤细胞生长的ROS雅普通路，因此可能是一种有效的抗癌药物。YAP 1及其辅因子TAZ在细胞增殖、迁移和侵袭中起关键作用，这些TEAD转录辅激活因子的异常激活在人类和小鼠的多种癌症中被发现。我们使用高度灵敏的荧光素酶报告系统筛选有效的YAP 1/TAZ抑制剂的化学文库，以监测细胞中的YAP 1/TAZ-TEAD转录活性。我们发现，土木香内酯主要靶向ROS雅普通路驱动肿瘤细胞生长，因此可能是一种有效的抗癌药物。
Yes‐associated protein 1 (YAP1) and its paralogue PDZ‐binding motif (TAZ) play pivotal roles in cell proliferation, migration, and invasion, and abnormal activation of these TEAD transcriptional coactivators is found in diverse cancers in humans and mice. Targeting YAP1/TAZ signaling is thus a promising therapeutic avenue but, to date, few selective YAP1/TAZ inhibitors have been effective against cancer cells either in vitro or in vivo. We screened chemical libraries for potent YAP1/TAZ inhibitors using a highly sensitive luciferase reporter system to monitor YAP1/TAZ‐TEAD transcriptional activity in cells. Among 29 049 low‐molecular‐weight compounds screened, we obtained nine hits, and the four of these that were the most effective shared a core structure with the natural product alantolactone (ALT). We also tested 16 other structural derivatives of ALT and found that natural ALT was the most efficient at increasing ROS‐induced LATS kinase activities and thus YAP1/TAZ phosphorylation. Phosphorylated YAP1/TAZ proteins were subject to nuclear exclusion and proteosomic degradation such that the growth of ALT‐treated tumor cells was inhibited both in vitro and in vivo. Our data show for the first time that ALT can be used to target the ROS‐YAP pathway driving tumor cell growth and so could be a potent anticancer drug. YAP1 and its paralogue TAZ play pivotal roles in cell proliferation, migration, and invasion, and abnormal activation of these TEAD transcriptional coactivators is found in diverse cancers in humans and mice. We screened chemical libraries for potent YAP1/TAZ inhibitors using a highly sensitive luciferase reporter system to monitor YAP1/TAZ‐TEAD transcriptional activity in cells. We found that alantolactone primarily targets the ROS‐YAP pathway driving tumor cell growth and so could be a potent anticancer drug.
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影响因子：
5.7
作者：
Maehama T;Nishio M;Otani J;Mak TW;Suzuki A
通讯作者：
Suzuki A
影响因子：
4.8
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通讯作者：
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影响因子：
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