American Association for Cancer Research
00085472can170859-sup-180888_2_supp_4150356_9sw49c.pptx (2.18 MB)

Supplementary Figures 1-8 from GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome

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posted on 2023-03-31, 00:41 authored by Peng Li, Evan Wuthrick, Jeff A. Rappaport, Crystal Kraft, Jieru E. Lin, Glen Marszalowicz, Adam E. Snook, Tingting Zhan, Terry M. Hyslop, Scott A. Waldman

Supplementary Figure 1. Silencing p53 expression in intestine of p53int-/- mice eliminates phospho-p53 responses to DNA damage induced by radiation. Supplementary Figure 2. Silencing p53 expression in intestine of p53int-/- mice amplifies RIGS-related toxicity. Supplementary Figure 3. Littermates are utilized to minimize the effect of genetic backgrounds in transgenic mice. Supplementary Figure 4. HCT116 cells do not exhibit GUCY2C ligand binding. Supplementary Figure 5. Total body irradiation induces gastrointestinal injury. Supplementary Figure 6. Hormone expression is preserved in RIGS in Gucy2c-/- mice. Supplementary Figure 7. Oral ST fails to oppose RIGS in the absence of GUCY2C. Supplementary Figure 8. Silencing p53 expression in intestine of p53int-/- mice does not affect apoptosis in RIGS.



Kimmel Cancer Center of Thomas Jefferson University



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.