Alantolactone is a natural product that potently inhibits YAP1/TAZ via promotion of ROS accumulation

Keisuke Nakatani, Tomohiko Maehama, Miki Nishio, Junji Otani, Keiko Yamaguchi, Miki Fukumoto, Hiroki Hikasa, Shinji Hagiwara, Hiroshi Nishina, Tak Wah Mak, Teruki Honma, Yasumitsu Kondoh (+3 others)
2021 Cancer Science  
YAP1 and its paralogue TAZ play pivotal roles in cell proliferation, migration and invasion, and abnormal activation of these TEAD transcriptional co-activators 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
more » ... system to monitor YAP1/TAZ-TEAD transcriptional activity in cells. Among 29,049 low-molecular-weight compounds screened, we obtained 9 hits, and the 4 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 may be a potent anti-cancer drug.
doi:10.1111/cas.15079 pmid:34289205 fatcat:d4dbtpai2vb4jl46ia6qme74qe