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GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome
- Source :
- Cancer Research. 77:5095-5106
- Publication Year :
- 2017
- Publisher :
- American Association for Cancer Research (AACR), 2017.
-
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.
- Subjects :
- Male
0301 basic medicine
Cancer Research
Lymphoma
Receptors, Peptide
Guanylin
Melanoma, Experimental
Paracrine Communication
Receptors, Enterotoxin
Apoptosis
Biology
Article
Gastrointestinal Hormones
Irritable Bowel Syndrome
Mice
03 medical and health sciences
chemistry.chemical_compound
Paracrine signalling
0302 clinical medicine
Tumor Cells, Cultured
Animals
Humans
Natriuretic Peptides
Mitotic catastrophe
Cell Proliferation
Gastrointestinal Tract
Mice, Inbred C57BL
Radiation Injuries, Experimental
030104 developmental biology
Receptors, Guanylate Cyclase-Coupled
Oncology
chemistry
Gamma Rays
030220 oncology & carcinogenesis
Colonic Neoplasms
Immunology
Cancer research
Female
Signal transduction
Signal Transduction
Uroguanylin
Hormone
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 77
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....2d7edc612e21f7d289eb1acefaa5171e