GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.

Peng Li, University of Florida
Evan Wuthrick, Ohio State University Comprehensive Cancer Center
Jeff A. Rappaport, Thomas Jefferson University
Crystal Kraft, Thomas Jefferson University
Jieru E. Lin, Thomas Jefferson University
Glen Marszalowicz, Thomas Jefferson University
Adam E. Snook, Thomas Jefferson University
Tingting Zhan, Thomas Jefferson University
Terry M. Hyslop, Duke University
Scott A. Waldman, Thomas Jefferson University

Document Type Article

This article has been peer reviewed. It is the authors' final version prior to publication in Cancer Research

Volume 77, Issue 18, September 2017, Pages 5095-5106.

The published version is available at DOI: 10.1158/0008-5472.CAN-17-0859. Copyright © AACR


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.