Periplogenin suppresses the growth of esophageal squamous cell carcinoma in vitro and in vivo by targeting STAT3

Yamei Hu, Fangfang Liu, Xuechao Jia, Penglei Wang, Tingxuan Gu, Hui Liu, Tingting Liu, Huifang Wei, Hanyong Chen, Jiuzhou Zhao, Ran Yang, Yingying Chen, Zigang Dong, Kang Dong Liu

Research output: Contribution to journalArticlepeer-review

Abstract

The mortality rate of esophageal squamous cell carcinoma (ESCC) is higher than that of other cancers worldwide owing to a lack of therapeutic targets and related drugs. This study aimed to find new drugs by targeting an efficacious therapeutic target in ESCC patients. Signal transducer and activator of transcription 3 (STAT3) is hyperactive in ESCC. Herein, we identified a novel STAT3 inhibitor, periplogenin, which strongly inhibited phosphorylation of STAT3 at Tyr705. Docking models and pull-down assays revealed that periplogenin bound directly and specifically to STAT3, leading to significant suppression of subsequent dimerization, nuclear import, and transcription activities. In addition, STAT3 knockdown cell lines were insensitive to periplogenin, whereas in contrast, STAT3-overexpressing cells were more sensitive to periplogenin, indicating that STAT3 was a target of periplogenin. Intraperitoneally administered periplogenin exhibited efficacious therapeutic effects in ESCC patient-derived xenograft models and dramatically impaired the phosphorylation of STAT3 and expression levels of STAT3-mediated downstream genes. Thus, our study demonstrated that periplogenin acted as a new STAT3 inhibitor, suppressing the growth of ESCC in vitro and in vivo, providing a basis for its potential application in ESCC treatment and prevention.

Original languageEnglish (US)
Pages (from-to)3942-3958
Number of pages17
JournalOncogene
Volume40
Issue number23
DOIs
StatePublished - Jun 2021

Bibliographical note

Funding Information:
Acknowledgements This work was supported by a grant from the National Science Foundation of China (No. 81872335); Henan Key Science and Technology Program 161100510300; National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (No. 2018ZX09711002). We thank Kyle Vaughn Laster, PhD, from China-US (Henan) Hormel Cancer Institute for polishing parts of this manuscript.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article

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