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GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.
- Source :
-
Cancer research [Cancer Res] 2017 Sep 15; Vol. 77 (18), pp. 5095-5106. - Publication Year :
- 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 .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Animals
Apoptosis radiation effects
Cell Proliferation radiation effects
Colonic Neoplasms enzymology
Colonic Neoplasms pathology
Colonic Neoplasms radiotherapy
Female
Gastrointestinal Hormones metabolism
Humans
Irritable Bowel Syndrome enzymology
Irritable Bowel Syndrome etiology
Lymphoma enzymology
Lymphoma pathology
Lymphoma radiotherapy
Male
Melanoma, Experimental enzymology
Melanoma, Experimental pathology
Melanoma, Experimental radiotherapy
Mice
Mice, Inbred C57BL
Natriuretic Peptides metabolism
Paracrine Communication radiation effects
Radiation Injuries, Experimental enzymology
Radiation Injuries, Experimental etiology
Receptors, Enterotoxin
Signal Transduction radiation effects
Tumor Cells, Cultured
Gamma Rays adverse effects
Gastrointestinal Tract radiation effects
Irritable Bowel Syndrome prevention & control
Radiation Injuries, Experimental prevention & control
Receptors, Guanylate Cyclase-Coupled metabolism
Receptors, Peptide metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 77
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 28916678
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-17-0859