EPAC inhibitor suppresses angiogenesis and tumor growth of triple-negative breast cancer

Zishuo Li, Qiao Liu, Yuhao Cai, Na Ye, Zinan He, Yuying Yao, Yi Ding, Pingyuan Wang, Cuiling Qi, Lingyun Zheng, Lijing Wang, Jia Zhou, Qian Qian Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive. Main methods: We employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice. Key findings: Inhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway. Conclusions: Our findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.

Original languageEnglish (US)
Article number167114
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1870
Issue number4
DOIs
StatePublished - Apr 2024

Keywords

  • Angiogenesis
  • cancer therapeutics
  • EPAC inhibitor
  • NY0123
  • Triple-negative breast cancer
  • Tumor growth

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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