College of Pharmacy, Jinan University, Guangzhou 510632, Guangdong, PR China.
Department of Pharmacology, School of Medicine, Jinan University, Guangzhou 510632, Guangdong, PR China.
Biochem Biophys Res Commun. 2014 Mar 21;445(4):795-801. doi: 10.1016/j.bbrc.2014.02.022. Epub 2014 Feb 12.
It has been reported that acidic fibroblast growth factor (aFGF) is expressed in breast cancer and via interactions with fibroblast growth factor receptors (FGFRs) to promote the stage and grade of the disease. Thus, aFGF/FGFRs have been considered essential targets in breast cancer therapy. We identified a specific aFGF-binding peptide (AGNWTPI, named AP8) from a phage display heptapeptide library with aFGF after four rounds of biopanning. The peptide AP8 contained two (TP) amino acids identical and showed high homology to the peptides of the 182-188 (GTPNPTL) site of high-affinity aFGF receptor FGFR1. Functional analyses indicated that AP8 specifically competed with the corresponding phage clone A8 for binding to aFGF. In addition, AP8 could inhibit aFGF-stimulated cell proliferation, arrested the cell cycle at the G0/G1 phase by increasing PA2G4 and suppressing Cyclin D1 and PCNA, and blocked the aFGF-induced activation of Erk1/2 and Akt kinase in both breast cancer cells and vascular endothelial cells. Therefore, these results indicate that peptide AP8, acting as an aFGF antagonist, is a promising therapeutic agent for the treatment of breast cancer.
据报道，酸性成纤维细胞生长因子（aFGF）在乳腺癌中表达，并通过与成纤维细胞生长因子受体（FGFRs）相互作用来促进疾病的阶段和分级。因此，aFGF/FGFRs 被认为是乳腺癌治疗的重要靶点。我们从经过四轮生物淘选的 aFGF 噬菌体展示七肽库中鉴定出一种特异性的 aFGF 结合肽（AGNWTPI，命名为 AP8）。肽 AP8 包含两个（TP）氨基酸相同，与高亲和力 aFGF 受体 FGFR1 的 182-188（GTPNPTL）位点的肽具有高度同源性。功能分析表明，AP8 特异性地与相应的噬菌体克隆 A8 竞争结合 aFGF。此外，AP8 可以通过增加 PA2G4 并抑制 Cyclin D1 和 PCNA 来抑制 aFGF 刺激的细胞增殖，将细胞周期阻滞在 G0/G1 期，并阻断 aFGF 诱导的乳腺癌细胞和血管内皮细胞中 Erk1/2 和 Akt 激酶的激活。因此，这些结果表明，肽 AP8 作为一种 aFGF 拮抗剂，是治疗乳腺癌的一种很有前途的治疗剂。
