The Guanylate Cyclase C—cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia

Abstract

Guanylate cyclase C (GUCY2C) is a transmembrane receptor expressed on the luminal aspect of the intestinal epithelium. Its ligands include bacterial heat-stable enterotoxins responsible for traveler's diarrhea, the endogenous peptide hormones uroguanylin and guanylin, and the synthetic agents, linaclotide, plecanatide, and dolcanatide. Ligand-activated GUCY2C catalyzes the synthesis of intracellular cyclic GMP (cGMP), initiating signaling cascades underlying homeostasis of the intestinal epithelium. Mouse models of GUCY2C ablation, and recently, human populations harboring GUCY2C mutations, have revealed the diverse contributions of this signaling axis to epithelial health, including regulating fluid secretion, microbiome composition, intestinal barrier integrity, epithelial renewal, cell cycle progression, responses to DNA damage, epithelial-mesenchymal cross-talk, cell migration, and cellular metabolic status. Because of these wide-ranging roles, dysregulation of the GUCY2C-cGMP signaling axis has been implicated in the pathogenesis of bowel transit disorders, inflammatory bowel disease, and colorectal cancer. This review explores the current understanding of cGMP signaling in the intestinal epithelium and mechanisms by which it opposes intestinal injury. Particular focus will be applied to its emerging role in tumor suppression. In colorectal tumors, endogenous GUCY2C ligand expression is lost by a yet undefined mechanism conserved in mice and humans. Further, reconstitution of GUCY2C signaling through genetic or oral ligand replacement opposes tumorigenesis in mice. Taken together, these findings suggest an intriguing hypothesis that colorectal cancer arises in a microenvironment of functional GUCY2C inactivation, which can be repaired by oral ligand replacement. Hence, the GUCY2C signaling axis represents a novel therapeutic target for preventing colorectal cancer.

Mechanical Stimuli Affect Escherichia coli Heat-Stable Enterotoxin-Cyclic GMP Signaling in a Human Enteroid Intestine-Chip Model

“…Flow and flow plus stretch were important for both apical and basolateral cGMP secretion, with either small or no increases occurring under static conditions. We can only speculate why the epithelial cells control intracellular cGMP content so carefully, but the well-described role of intracellular cGMP as an inhibitor of proliferation would predict that it is likely to be stringently regulated (35).…”

Uroguanylin-decorated Nanosystems Containing Etoposide, a Potential Targeted Combination Therapy for Colorectal Cancer

“…In this work, the decoration of SNs with UroGm combined with the encapsulation of the anticancer drug etoposide was selected to promote a synergistic effect of both drugs. This synergy could be justi ed due to the joint activation of cGMP-AKT axis by the UroGm and the DNA damage response triggered by Etp [52,53], and to an improved uptake of Etp due to its encapsulation into a nanosystem [54,55].…”

Mechanical Stimuli Affect E. Coli Heat Stable Enterotoxin (ST)-Cyclic GMP Signaling in a Human Enteroid Intestine-Chip Diarrhea Model

“…Flow and flow plus stretch were important for both apical and basolateral cGMP secretion with either small or no increases occurring under static conditions. We can only speculate why the epithelial cells control intracellular cGMP content so carefully, but the well-described role of intracellular cGMP as an inhibitor of proliferation would predict that it is likely to be stringently regulated (39).…”