Targeting the Paracrine Hormone-Dependent Guanylate cyclase/cGMP/Phosphodiesterases Signaling Pathway for Colorectal Cancer Prevention

Publication date: Available online 3 September 2018Source: Seminars in Cancer BiologyAuthor(s): N.S. Yarla, H. Gali, G. Pathuri, S. Smriti, V. Madka, J. Panneerselvam, G. Kumar, M Farooqui, C.V. RaoAbstractColorectal cancer (CRC) is one of the leading causes of cancer related-deaths. The risk of development of CRC is complex and multifactorial, and includes disruption of homeostasis of the intestinal epithelial layer mediated though dysregulations of tumor suppressing/promoting signaling pathways. Guanylate cyclase 2C (GUCY2C), a membrane-bound guanylate cyclase receptor, is present in the apical membranes of intestinal epithelial cells and maintains homeostasis. GUCY2C is activated upon binding of paracrine hormones (guanylin and uroguanylin) that lead to formation of cyclic GMP from GTP and activation of downstream signaling pathways that are associated with normal homeostasis. Dysregulation/suppression of the GUCY2C-mediated signaling promotes CRC tumorigenesis. High-calorie diet-induced obesity is associated with deficiency of guanylin expression and silencing of GUCY2C-signaling in colon epithelial cells, leading to tumorigenesis. Thus, GUCY2C agonists, such as linaclotide, exhibit considerable role in preventing CRC tumorigenesis. However, phosphodiesterases (PDEs) are elevated in intestinal epithelial cells during CRC tumorigenesis and block GUCY2C-mediated signaling by degrading cyclic GMP to 5`-GMP. PDE5-specific inhibitors, such as sildenafil, show considerable anti...
Source: Seminars in Cancer Biology - Category: Cancer & Oncology Source Type: research