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© 2021. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

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.

Details

Title
Alantolactone is a natural product that potently inhibits YAP1/TAZ through promotion of reactive oxygen species accumulation
Author
Nakatani, Keisuke 1 ; Maehama, Tomohiko 2   VIAFID ORCID Logo  ; Nishio, Miki 2 ; Otani, Junji 2 ; Yamaguchi, Keiko 2 ; Fukumoto, Miki 2 ; Hikasa, Hiroki 3 ; Hagiwara, Shinji 4 ; Nishina, Hiroshi 5 ; Mak, Tak Wah 6 ; Honma, Teruki 7 ; Kondoh, Yasumitsu 8 ; Osada, Hiroyuki 8 ; Yoshida, Minoru 9 ; Suzuki, Akira 10   VIAFID ORCID Logo 

 Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan; Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; Bio Science and Engineering Laboratory, Research and Development Management Headquarters, FujiFilm Corporation, Kanagawa, Japan 
 Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan 
 Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan 
 Bio Science and Engineering Laboratory, Research and Development Management Headquarters, FujiFilm Corporation, Kanagawa, Japan 
 Medical Research Institute, Department of Developmental and Regenerative Biology, Tokyo Medical and Dental University, Tokyo, Japan 
 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Pathology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 
 RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan 
 Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan 
 Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Japan; Department of Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan 
10  Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan; Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan 
Pages
4303-4316
Section
ORIGINAL ARTICLES
Publication year
2021
Publication date
Oct 2021
Publisher
John Wiley & Sons, Inc.
ISSN
13479032
e-ISSN
13497006
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2578178435
Copyright
© 2021. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.