Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP

The enteric peptides, guanylin and uroguanylin, are local regulators of int estinal secretion by activation of receptor-guanylate cyclase (R-GC) signal ing molecules that produce cyclic GMP (cGMP) and stimulate the cystic fibro sis transmembrane conductance regulator-dependent secretion of Cl- and HCO3 -. Our experiments demonstrate that mRNA transcripts for guanylin and urogu anylin are markedly reduced in colon polyps and adenocarcinomas, In contras t, a specific uroguanylin-R-GC, R-GCC, is expressed in polyps and adenocarc inomas at levels comparable with normal colon mucosa, Activation of R-GCC b y uroguanylin in vitro inhibits the proliferation of T84 colon cells and el icits profound apoptosis in human colon cancer cells, T84, Therefore, down- regulation of gene expression and loss of the peptides may interfere with r enewal and/or removal of the epithelial cells resulting in the formation of polyps, which can progress to malignant cancers of the colon and rectum, O ral replacement therapy with human uroguanylin was used to evaluate its eff ects on the formation of intestinal polyps in the Min/+ mouse model for col orectal cancer. Uroguanylin significantly reduces the number of polyps foun d in the intestine of Min/+ mice by similar to 50% of control. Our findings suggest that uroguanylin and guanylin regulate the turnover of epithelial cells within the intestinal mucosa via activation of a cGMP signaling mecha nism that elicits apoptosis of target enterocytes, The intestinal R-GC sign aling molecules for guanylin regulatory peptides are promising targets for prevention and/or therapeutic treatment of intestinal polyps and cancers by oral administration of human uroguanylin.