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GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.

ABSTRACT: High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin have recently emerged as one paracrine axis defending intestinal mucosal integrity against mutational, chemical, and inflammatory injury. Here, we reveal a role for the GUCY2C paracrine axis in compensatory mechanisms opposing RIGS. Eliminating GUCY2C signaling exacerbated RIGS, amplifying radiation-induced mortality, weight loss, mucosal bleeding, debilitation, and intestinal dysfunction. Durable expression of GUCY2C, guanylin, and uroguanylin mRNA and protein by intestinal epithelial cells was preserved following lethal irradiation inducing RIGS. Oral delivery of the heat-stable enterotoxin (ST), an exogenous GUCY2C ligand, opposed RIGS, a process requiring p53 activation mediated by dissociation from MDM2. In turn, p53 activation prevented cell death by selectively limiting mitotic catastrophe, but not apoptosis. These studies reveal a role for the GUCY2C paracrine hormone axis as a novel compensatory mechanism opposing RIGS, and they highlight the potential of oral GUCY2C agonists (Linzess; Trulance) to prevent and treat RIGS in cancer therapy and nuclear disasters. Cancer Res; 77(18); 5095-106. ©2017 AACR.

SUBMITTER: Li P

PROVIDER: S-EPMC5678756 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.

Li Peng P Wuthrick Evan E Rappaport Jeff A JA Kraft Crystal C Lin Jieru E JE Marszalowicz Glen G Snook Adam E AE Zhan Tingting T Hyslop Terry M TM Waldman Scott A SA

Cancer research 20170901 18

High doses of ionizing radiation induce acute damage to epithelial cells of the gastrointestinal (GI) tract, mediating toxicities restricting the therapeutic efficacy of radiation in cancer and morbidity and mortality in nuclear disasters. No approved prophylaxis or therapy exists for these toxicities, in part reflecting an incomplete understanding of mechanisms contributing to the acute radiation-induced GI syndrome (RIGS). Guanylate cyclase C (GUCY2C) and its hormones guanylin and uroguanylin ...[more]

PMID: 28916678

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Project description:GUCY2C is the intestinal receptor for the paracrine hormones guanylin and uroguanylin that converts guanosine-5'-triphosphate to cyclic guanosine monophosphate (cGMP). 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 colon cancer cells by microscopy, immunoblot, and functional analyses. Microarray analyses compared gene expression profiles of intestine cell from Gucy2c(-/-) and wild-type mice. v akt murine thymoma viral oncogene homolog (AKT) regulation and signaling were examined, and the role of AKT in GUCY2C-dependent tumorigenesis was defined in Gucy2c(-/-)Akt1(-/-) mice.The size and number of intestinal crypts increased in Gucy2c(-/-) mice; the associated epithelial cells showed accelerated proliferation, increased glycolysis, and reduced oxidative phosphorylation, which was reversed by oral administration of cGMP. Conversely, activating guanylyl cyclase C in human colon cancer cells delayed cell-cycle progression, decreased DNA synthesis and colony formation, reduced glycolysis, and increased mitochondrial adenosine triphosphate 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 after 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 metabolism of intestinal epithelial cells by inactivating AKT signaling. This receptor and its ligands, which are paracrine hormones, might be novel candidates for anticolorectal cancer therapy.

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GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.

Publications

GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.

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