Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
Eur J Pharmacol. 2021 Jan 15;891:173727. doi: 10.1016/j.ejphar.2020.173727. Epub 2020 Nov 5.
Peptidases are emerging as promising drug targets in tumour suppression. Neprilysin, also known as neutral endopeptidase, is a cell surface peptidase that degrades various peptides such as angiotensin II, endothelin I, Substance P, etc., and reduces their local concentration. Neprilysin is expressed in various tissues such as kidney, prostate, lung, breast, brain, intestine, adrenal gland, etc. The tumour-suppressor mechanisms of neprilysin include its peptidase activity that degrades mitogenic growth factors such as fibroblast growth factor-2 and insulin-like growth factors, and the protein-protein interaction of neprilysin with phosphatase and tensin homolog, focal adhesion kinase, ezrin/radixin/moesin, and phosphoinositide 3-kinase. Studies have shown that the levels of neprilysin play an important role in malignancies. NEP is downregulated in prostate, renal, lung, breast, urothelial, cervical, hepatic cancers, etc. Histone deacetylation and hypermethylation of the neprilysin promoter region are the common mechanisms involved in the downregulation of neprilysin. Downregulation of the peptidase promotes angiogenesis, cell survival and cell migration. This review presents an overview of the role of neprilysin in malignancy, the tumour suppression mechanisms of neprilysin, the epigenetic mechanisms responsible for downregulation of neprilysin, and the potential pharmacological approaches to upregulate neprilysin levels and its activity.
肽酶作为肿瘤抑制的潜在药物靶点正在兴起。 中性内肽酶，也称为 Neprilysin，是一种细胞表面肽酶，可降解血管紧张素 II、内皮素 I、P 物质等多种肽，并降低其局部浓度。 Neprilysin 表达于肾脏、前列腺、肺、乳腺、脑、肠、肾上腺等多种组织中。 Neprilysin 的肿瘤抑制机制包括其肽酶活性，可降解成纤维细胞生长因子-2 和胰岛素样生长因子等有丝分裂原生长因子，以及 Neprilysin 与磷酸酶和张力蛋白同系物、粘着斑激酶、埃兹蛋白/根蛋白/膜突蛋白和磷酸肌醇 3-激酶的蛋白-蛋白相互作用。研究表明 Neprilysin 的水平在恶性肿瘤中起着重要作用。 Neprilysin 在前列腺癌、肾癌、肺癌、乳腺癌、尿路上皮癌、宫颈癌、肝癌等中下调。 Neprilysin 启动子区域的组蛋白去乙酰化和高甲基化是 Neprilysin 下调的常见机制。 肽酶的下调促进血管生成、细胞存活和细胞迁移。 本文综述了 Neprilysin 在恶性肿瘤中的作用、Neprilysin 的肿瘤抑制机制、负责 Neprilysin 下调的表观遗传机制以及上调 Neprilysin 水平及其活性的潜在药理学方法。
