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Experimental Therapeutics |
Cancer Chemoprevention Group Nutrition Sector, [K. S., H. H. Y., K. K., J. Y. W., S. Z. A., S. S. B.], Searle Research and Development [M. G. C.], Monsanto Life Sciences Company, St. Louis, Missouri 63167, and Truman Memorial Veterans Affairs Hospital [S. L. E., Y. W., B. W. M, L. R. F.], Departments of Pharmacology [S. L. E., Y. W., N. S. J., H. D. K., L. R. F.] and Surgery [B. W. M.], Missouri University, Columbia, Missouri 65212
The enteric peptides, guanylin and uroguanylin, are local regulators of
intestinal secretion by activation of receptor-guanylate cyclase (R-GC)
signaling molecules that produce cyclic GMP (cGMP) and stimulate the
cystic fibrosis transmembrane conductance regulator-dependent secretion
of Cl- and HCO3-. Our experiments
demonstrate that mRNA transcripts for guanylin and uroguanylin are
markedly reduced in colon polyps and adenocarcinomas. In contrast, a
specific uroguanylin-R-GC, R-GCC, is expressed in polyps and
adenocarcinomas at levels comparable with normal colon mucosa.
Activation of R-GCC by uroguanylin in vitro inhibits the
proliferation of T84 colon cells and elicits profound apoptosis in
human colon cancer cells, T84. Therefore, down-regulation of gene
expression and loss of the peptides may interfere with renewal and/or
removal of the epithelial cells resulting in the formation of polyps,
which can progress to malignant cancers of the colon and rectum. Oral
replacement therapy with human uroguanylin was used to evaluate its
effects on the formation of intestinal polyps in the
Min/+ mouse model for colorectal cancer. Uroguanylin
significantly reduces the number of polyps found in the intestine of
Min/+ mice by 
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
mechanism that elicits apoptosis of target enterocytes. The intestinal
R-GC signaling 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.
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