Muscone derivative ZM-32 inhibits breast tumor angiogenesis by suppressing HuR-mediated VEGF and MMP9 expression.

Abstract

Inhibition of tumor angiogenesis is a highly effective strategy for cancer treatment. Human antigen R (HuR), an RNA-binding protein, is overexpressed in many cancers and regulates the mRNAs of multiple angiogenic factors by binding to the adenylate-uridylate-rich element in their 3' untranslated region. HuR protein has been demonstrated to be an important regulatory factor in macrophage-mediated angiogenesis, a process in which macrophages are critical for tumor progression. Muscone is a synthetic equivalent of musk, and recent studies have shown that it has a regulatory effect on angiogenesis. In this study, we synthesized five series of muscone derivatives and discovered that compound ZM-32 was effective in preventing HuR RRM1/2-Vegf-a mRNA complex formation. ZM-32 bound to HuR RRM1/2 protein with a KD value of 521.7 nmol/L. Furthermore, ZM-32 inhibited endothelial cell proliferation, migration, and tubule formation, and suppressed the VEGF/VEGFR2/ERK1/2 signaling axis mediated by macrophages in vitro. We also demonstrated that ZM-32 effectively prevented the proliferation and migration of breast cancer cells and inhibited the growth and angiogenesis of MDA-MB-231 xenograft tumors without any obvious toxicity in vivo. Mechanistically, exposure to ZM-32 influenced the mRNA stability of Vegf-a and Mmp9 in a HuR-dependent manner in both macrophages and MDA-MB-231 cells. Thus, in this study we identified a new muscone derivative, ZM-32, with anti-angiogenesis effects mediated via targeting HuR in breast cancer, that may become a potentially valuable lead compound for anti-cancer angiogenesis.

• Authors: Liu-Qing Yang, Shao-Peng Yu, Yan-Tao Yang, Yi-Shuang Zhao, Fei-Yun Wang, Yao Chen, Qing-Hua Li, Ping Tian, Yu-Ying Zhu, Jian-Ge Zhang, Guo-Qiang Lin
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 136 Pg. 111265 (Apr 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 33450490 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Cycloparaffins
• ELAV-Like Protein 1
• ELAVL1 protein, human
• RNA, Messenger
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• MMP9 protein, human
• Matrix Metalloproteinase 9

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Breast Neoplasms (drug therapy, enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cycloparaffins (pharmacology)
• ELAV-Like Protein 1 (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Macrophages (drug effects, metabolism)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Mice, Nude
• Neovascularization, Pathologic
• RAW 264.7 Cells
• RNA Stability
• RNA, Messenger (genetics, metabolism)
• Signal Transduction
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Xenograft Model Antitumor Assays