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Formononetin represses cervical tumorigenesis by interfering with the activation of PD-L1 through MYC and STAT3 downregulation.

Abstract
A. membranaceus is a traditional Chinese medicine that regulates blood sugar levels, suppresses inflammation, protects the liver, and enhances immunity. In addition, A. membranaceus is also widely used in diet therapy and is a well-known health tonic. Formononetin is a natural product isolated from A. membranaceus that has multiple biological functions, including anti-cancer activity. However, the mechanism by which formononetin inhibits tumor growth is not fully understood. In this present study, we demonstrated that formononetin suppresses PD-L1 protein synthesis via reduction of MYC and STAT3 protein expression. Furthermore, formononetin markedly reduced the expression of MYC protein via the RAS/ERK signaling pathway and inhibited STAT3 activation through JAK1/STAT3 pathway. Co-immunoprecipitation experiments illustrated that formononetin suppresses protein expression of PD-L1 by interfering with the interaction between MYC and STAT3. Meanwhile, formononetin promoted PD-L1 protein degradation via TFEB and TFE3-mediated lysosome biogenesis. T cell killing assay revealed that formononetin could enhance the activity of cytotoxic T lymphocytes (CTLs) and restore ability to kill tumor cells in a co-culture system of T cells and tumor cells. In addition, formononetin inhibited cell proliferation, tube formation, cell migration, and promoted tumor cell apoptosis by suppressing PD-L1. Finally, the inhibitory effect of formononetin on tumor growth was confirmed in a murine xenograft model. The present study revealed the anti-tumor potential of formononetin, and the findings should support further research and development of anti-cancer drugs for cervical cancer.
AuthorsJing Ying Wang, Ming Wen Jiang, Ming Yue Li, Zhi Hong Zhang, Yue Xing, MyongHak Ri, Cheng Hua Jin, Guang Hua Xu, Lian Xun Piao, Hong Lan Jin, Juan Ma, Yong Jin, Hong Xiang Zuo, Xuejun Jin
JournalThe Journal of nutritional biochemistry (J Nutr Biochem) Vol. 100 Pg. 108899 (02 2022) ISSN: 1873-4847 [Electronic] United States
PMID34748924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2021. Published by Elsevier Inc.
Chemical References
  • Antineoplastic Agents
  • B7-H1 Antigen
  • CD274 protein, human
  • Isoflavones
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • formononetin
Topics
  • Antineoplastic Agents (pharmacology)
  • Apoptosis
  • B7-H1 Antigen (metabolism)
  • Carcinogenesis (drug effects)
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Coculture Techniques
  • Down-Regulation
  • Female
  • Human Umbilical Vein Endothelial Cells (cytology, metabolism, physiology)
  • Humans
  • Isoflavones (pharmacology)
  • Lysosomes (metabolism)
  • Organelle Biogenesis
  • Proto-Oncogene Proteins c-myc (genetics, metabolism)
  • STAT3 Transcription Factor (genetics, metabolism)
  • Signal Transduction
  • T-Lymphocytes (immunology)
  • Uterine Cervical Neoplasms (immunology, physiopathology)
  • Xenograft Model Antitumor Assays

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