Background & Aims
Gucy2c is the intestinal cell receptor for the paracrine hormones guanylin and uroguanylin that converts GTP to cyclic (c)GMP. It functions as a tumor suppressor; its loss disrupts intestinal homeostasis and promotes tumorigenesis. We investigated the effects of Gucy2c loss on intestinal cell proliferation, metabolism, signaling, and tumorigenesis in mice.
Intestinal cell proliferation and metabolism were examined in Gucy2c−/− and wild-type mice and human colon cancer cells by microscopy, immunoblot, and functional analyses. AKT regulation and signaling were examined and the role of AKT in Gucy2c-dependent tumorigenesis was defined in Gucy2c−/−Akt1−/− mice. Microarray analyses compared gene expression profiles of intestine of Gucy2c−/− and wild-type mice.
The size and number of intestinal crypts increased in Gucy2c−/− mice; the associated epithelial cells exhibited accelerated proliferation, increased glycolysis, and reduced oxidative phosphorylation, which was reversed by oral administration of cGMP. Conversely, activating GUCY2C in human colon cancer cells delayed cell cycle progression (inhibiting DNA synthesis and colony formation), reduced glycolysis, and increased mitochondrial ATP production. AKT signaling pathways were activated in intestines of Gucy2c−/− mice, associated with increased AKT phosphorylation. Disruption of AKT activity, pharmacologically or genetically, reduced DNA synthesis, proliferation, and glycolysis and increased mitochondrial biogenesis. Intestinal tumorigenesis increased following administration of azoxymethane to Gucy2c−/− mice, compared with wild-type mice, but was eliminated in Gucy2c−/−Akt1−/− mice.
Gucy2c is a tumor suppressor that controls proliferation and survival of intestinal epithelial cells by inactivating AKT signaling. This receptor and its ligands, which are paracrine hormones, might be novel candidates for anti-colorectal cancer therapy.