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ZM-32 inhibits the growth and angiogenesis of breast tumor without obvious toxicity.
ZM-32 inhibits angiogenesis by preventing HuR RRM12-Vegf-a mRNA complex formation.
ZM-32 targets HuR and reduced mRNA stabilization both in tumor cells and macrophages.
HuR protein could be useful target for anti-angiogenesis drug screening.
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.El texto completo de este artículo está disponible en PDF.
Keywords : Muscone derivatives, Angiogenesis, Macrophage, HuR, Breast cancer
Vol 136Artículo 111265- avril 2021 Regresar al número
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