Tumour suppression through modulation of neprilysin signaling: A comprehensive review

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.