Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu 210042, P.R. China.
Int J Oncol. 2020 Nov;57(5):1203-1213. doi: 10.3892/ijo.2020.5119. Epub 2020 Sep 7.
EphA2 (EPH receptor A2) (erythropoietin‑producing hepatocellular receptor tyrosine kinase subtype A2) plays a crucial role in human cancers, and is a promising target for the development of new anticancer drugs. In this study, we showed that the interaction of Annexin A1 (ANXA1) and EphA2 increased EphA2 stability by inhibiting its proteasome degradation in gastric cancer (GC) and colon cancer (CC) cells, and the amino acid residues 20‑30 and 28‑30 of ANXA1 N terminal were responsible for binding and stabilizing EphA2. Based on the amino acid residues of ANXA1 responsible for binding EphA2, we developed ANXA1‑derived 3 amino acid‑long (SKG) and 11 amino acid‑long peptides (EYVQTVKSSKG) in fusion to cell‑penetrating peptide, named as A1(28‑30) and A1(20‑30) respectively, and found that A1(28‑30) and A1(20‑30) blocked the binding of ANXA1 with EphA2, targeted EphA2 degradation, and suppressed the growth of GC and CC cells in vitro and in mice. Our data demonstrated that ANXA1 was able to bind and stabilize EphA2 in GC and CC cells, and disruption of ANXA1‑EphA2 interaction by the two ANXA1‑derived peptides inhibited the growth of GC and CC cells by targeting EphA2 degradation, presenting a potential strategy for treating GC and CC with these peptides.
EphA2（EPH 受体 A2）（促红细胞生成素产生肝细胞受体酪氨酸激酶亚型 A2）在人类癌症中发挥着至关重要的作用，是开发新型抗癌药物的有前途的靶点。在这项研究中，我们表明 Annexin A1（ANXA1）与 EphA2 的相互作用通过抑制胃癌（GC）和结肠癌（CC）细胞中的蛋白酶体降解来增加 EphA2 的稳定性，并且 ANXA1 N 端的 20-30 个和 28-30 个氨基酸残基负责结合和稳定 EphA2。基于负责结合 EphA2 的 ANXA1 氨基酸残基，我们开发了与细胞穿透肽融合的 ANXA1 衍生的 3 个氨基酸长（SKG）和 11 个氨基酸长的肽（EYVQTVKSSKG），分别命名为 A1（28-30）和 A1（20-30），并发现 A1（28-30）和 A1（20-30）阻断了 ANXA1 与 EphA2 的结合，靶向 EphA2 降解，并抑制 GC 和 CC 细胞在体外和小鼠中的生长。我们的数据表明，ANXA1 能够在 GC 和 CC 细胞中结合和稳定 EphA2，并且这两种 ANXA1 衍生肽通过破坏 ANXA1-EphA2 相互作用靶向 EphA2 降解，抑制 GC 和 CC 细胞的生长，为用这些肽治疗 GC 和 CC 提供了一种潜在的策略。
