School of Basic Medical Sciences, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
Biochim Biophys Acta Mol Basis Dis. 2024 Apr;1870(4):167114. doi: 10.1016/j.bbadis.2024.167114. Epub 2024 Mar 4.
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.
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.
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.
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.
环磷酸腺苷（cAMP）直接激活蛋白 1（EPAC1）是鸟嘌呤核苷酸交换因子的主要同工型，在血管内皮细胞中高度表达，调节视网膜中的血管生成。血管生成导致的肿瘤内高微血管密度（MVD）是乳腺癌发展的原因。肿瘤细胞中 EPAC1 的下调可减少三阴性乳腺癌（TNBC）诱导的血管生成。然而，血管内皮细胞中表达的 Epac1 是否有助于 TNBC 的血管生成和肿瘤发展仍不清楚。
我们使用了 NY0123，这是一种先前确定的有效的 EPAC 抑制剂，通过血管内皮细胞、大鼠主动脉环、Matrigel plugs、鸡胚绒毛尿囊膜（CAM）和卵黄囊膜（YSM）测定，以及 TNBC 的鸡胚和小鼠体内异种移植肿瘤模型，来研究 EPAC1 在体外和体内的抗血管生成生物学作用。
用 NY0123 抑制血管内皮细胞中的 EPAC1 可显著抑制 TNBC 的血管生成和肿瘤生长。此外，NY0123 比报道的特定 EPAC 抑制剂工具化合物 ESI-09 具有更好的抑制效果。重要的是，抑制血管内皮细胞中的 EPAC1 调节了典型的血管生成信号网络，这不仅与血管内皮生长因子（VEGF）/血管内皮生长因子受体-2（VEGFR2）信号有关，还与 PI3K/AKT、MEK/ERK 和 Notch 途径有关。
我们的研究结果表明，EPAC1 可能是 TNBC 的有效抗血管生成治疗靶点，EPAC 抑制剂 NY0123 具有开发用于治疗 TNBC 的治疗潜力。
