Division of Pathophysiology, National Institute of Cholera and Enteric Diseases, P-33, CIT Road, Scheme-XM, Beliaghata, Kolkata, 700010, India.
Division of Clinical Medicine, National Institute of Cholera and Enteric Diseases, Kolkata, India.
Apoptosis. 2018 Dec;23(11-12):679-694. doi: 10.1007/s10495-018-1485-4.
A novel activating peptide was designed and synthesized from V. cholerae hemagglutinine protease (HAP) mediated cleavage site of mouse PAR1. The peptide "PFISED" interacts with PAR1 in a new site which is different from its thrombin mediated conventional activation site and induced a series of new downstream signaling pathways. The peptide showed apoptosis in human and mouse breast (MCF-7 and EAC) and colon (HT29 and CT26) cancer cells where as in the same peptide concentration in normal human breast epithelial cells (MCF-10A), normal human fibroblast cells (MRC-5), normal mouse peritoneal macrophage cells and normal mouse breast and colon tissues did not show any effect. Treatment with this peptide enhanced the survival kinetics of EAC induced mice. The peptide mediated apoptosis was inhibited in presence of PAR1 inhibitor and was significantly reduced in si-PAR1 treated cells that indicate the activating peptide "PFISED" induced PAR1 mediated apoptosis of colon and breast cancer cells. This peptide induced over expression and activation of PAR1 and its downstream MAP kinase and NFκB signaling pathways. These signaling pathways enhanced the cellular ROS level to kill malignant cells. We report a novel pro-apoptotic peptide which can selectively kill malignant cells via its specific target receptor PAR1 which is over expressed in the malignant cells and can be used as a molecular target therapy for cancer treatment.
从霍乱弧菌血凝素蛋白酶 (HAP) 介导的小鼠 PAR1 裂解位点设计并合成了一种新型激活肽。该肽“PFISED”与 PAR1 在一个不同于其凝血酶介导的常规激活位点的新位点相互作用，并诱导了一系列新的下游信号通路。该肽在人源和鼠源乳腺癌 (MCF-7 和 EAC) 和结肠癌 (HT29 和 CT26) 癌细胞中表现出凋亡，而在相同浓度的肽在正常人类乳腺上皮细胞 (MCF-10A)、正常人类成纤维细胞 (MRC-5)、正常鼠腹膜巨噬细胞和正常鼠乳腺和结肠组织中则没有显示出任何效果。用这种肽处理可增强 EAC 诱导的小鼠的存活动力学。在 PAR1 抑制剂存在的情况下，该肽介导的凋亡被抑制，并且在 si-PAR1 处理的细胞中显著减少，这表明激活肽“PFISED”诱导了 PAR1 介导的结肠癌和乳腺癌细胞凋亡。该肽诱导了 PAR1 及其下游 MAP 激酶和 NFκB 信号通路的过度表达和激活。这些信号通路增加了细胞内 ROS 水平以杀死恶性细胞。我们报告了一种新型促凋亡肽，它可以通过其在恶性细胞中过度表达的特定靶受体 PAR1 选择性杀死恶性细胞，可作为癌症治疗的分子靶向治疗。
