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Cancers (Basel). 2018 Nov 16;10(11). pii: E449. doi: 10.3390/cancers10110449.

Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation.

Ji X1, Song L2, Sheng L3, Gao A4, Zhao Y5, Han S6, Zhang Y7, Zhu C8, Zhao S9, Wang Z10, Xu B11, Li L12, Li J13,14, Tan N15,16, Zhao B17.

Author information

1
MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. jixinyan@zju.edu.cn.
2
School of Traditional Chinese Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China. songlihua4835@163.com.
3
The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, China. lsheng@simm.ac.cn.
4
The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, China. ahgao@simm.ac.cn.
5
MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. zhaoyang15@zju.edu.cn.
6
MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. shixunhan@foxmail.com.
7
MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. zhangyuchao0713@163.com.
8
MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. zucu@zju.edu.cn.
9
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China. liuzhengyirs@126.com.
10
School of Traditional Chinese Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China. wangzhe@cpu.edu.cn.
11
MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. bohanxu@zju.edu.cn.
12
Institute of Aging Research, Hangzhou Normal University, Hangzhou 311121, China. lili@hznu.edu.cn.
13
The National Center for Drug Screening, 189 Guoshoujing Road, Shanghai 201203, China. jli@simm.ac.cn.
14
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. jli@simm.ac.cn.
15
School of Traditional Chinese Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China. nhtan@cpu.edu.cn.
16
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China. nhtan@cpu.edu.cn.
17
MOE Key Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. binzhao@zju.edu.cn.

Abstract

The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation.

KEYWORDS:

RA-V; TAZ; YAP; cancer; hippo pathway; organ size; protein synthesis

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