Focal Adhesion Kinase-Dependent Role of the Soluble Form of Neurotensin Receptor-3/Sortilin in Colorectal Cancer Cell Dissociation

Abstract

The aim of the present review is to unravel the mechanisms of action of the soluble form of the neurotensin (NT) receptor-3 (NTSR3), also called Sortilin, in numerous physiopathological processes including cancer development, cardiovascular diseases and depression. Sortilin/NTSR3 is a transmembrane protein thought to exert multiple functions both intracellularly and at the level of the plasma membrane. The Sortilin/NTSR3 extracellular domain is released by shedding from all the cells expressing the protein. Although the existence of the soluble form of Sortilin/NTSR3 (sSortilin/NTSR3) has been evidenced for more than 10 years, the studies focusing on the role of this soluble protein at the mechanistic level remain rare. Numerous cancer cells, including colonic cancer cells, express the receptor family of neurotensin (NT), and particularly Sortilin/NTSR3. This review aims to summarize the functional role of sSortilin/NTSR3 characterized in the colonic cancer cell line HT29. This includes mechanisms involving signaling cascades through focal adhesion kinase (FAK), a key pathway leading to the weakening of cell–cell and cell–extracellular matrix adhesions, a series of events which could be responsible for cancer metastasis. Finally, some future approaches targeting the release of sNTSR3 through the inhibition of matrix metalloproteases (MMPs) are suggested.

Dimerization of sortilin regulates its trafficking to extracellular vesicles

“…Previous studies reported that serum sortilin levels are associated with cardiovascular risk, such as aortic calcification ( 31 ) and atherothrombosis ( 32 ), as well as depression ( 33 ). Soluble sortilin can also activate survival pathways in cancer cells ( 6 , 34 ). Therefore, it is important to understand whether soluble sortilin contributes to diseases through the formation of monomers and/or homodimers.…”

“…Sortilin, which is ubiquitously expressed and essential for proper function of many tissues and cell types, is a sorting receptor that directs target proteins, including growth factors, signaling receptors, and enzymes, to their destined location in the secretory or endocytic compartments of cells ( 4 ). Sortilin has conversely also emerged as a major cause of malignancies in a range of diseases ( 5 ), including cancer ( 6 – 9 ), type 2 diabetes mellitus ( 10 ), hypercholesterolemia ( 11 – 13 ), atherosclerosis ( 14 , 15 ), and neurodegenerative disorders ( 16 , 17 ), such as Alzheimer's disease ( 18 , 19 ). The atypical increase in intracellular trafficking by sortilin and its subsequent lysosomal degradation ( 16 ) or secretion ( 11 , 15 ) have been linked to the pathogenesis of the aforementioned diseases.…”

Screening differentially expressed genes of pancreatic cancer between Mongolian and Han people using bioinformatics technology

“…The FAK signaling pathway can integrate multiple extracellular signals to regulate the expression of downstream molecules, thereby controlling the proliferation and apoptosis of cells. This pathway is cascaded with multiple signal transduction pathways in the body and is the central link of intracellular and extracellular signal transduction [14,15].. A large number of studies have confirmed that the abnormal activation of FAK signaling pathway is closely related to the occurrence and development of various malignant tumors [16][17][18]. In the study of pancreatic cancer, Gao Z et al [19] reported that the overexpression of SRPX2 (Sushi repeat-containing protein, X-linked 2), which is dependent on the phosphorylation level of FAK, is closely related to the local invasion and distant metastasis of pancreatic cancer.…”

Screening differentially expressed genes of pancreatic cancer between Mongolian and Han people using bioinformatics technology

“…[14,15]. A large number of studies have confirmed that the abnormal activation of FAK signaling pathway is closely related to the occurrence and development of various malignant tumors [16][17][18].…”