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

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.

• Authors: 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, Kangdong Liu
• Journal: Oncogene (Oncogene) Vol. 40 Issue 23 Pg. 3942-3958 (06 2021) ISSN: 1476-5594 [Electronic] England
• PMID: 33986510 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• STAT3 Transcription Factor
• STAT3 protein, human
• Digitoxigenin
• periplogenin

Topics

• Aged
• Aged, 80 and over
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Digitoxigenin (analogs & derivatives, pharmacology)
• Esophageal Neoplasms (drug therapy, metabolism, pathology)
• Esophageal Squamous Cell Carcinoma (drug therapy, metabolism, pathology)
• Female
• Humans
• Male
• Middle Aged
• Phosphorylation (drug effects)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Survival Rate
• Xenograft Model Antitumor Assays