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GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.

Publication ,  Journal Article
Li, P; Wuthrick, E; Rappaport, JA; Kraft, C; Lin, JE; Marszalowicz, G; Snook, AE; Zhan, T; Hyslop, TM; Waldman, SA
Published in: Cancer research
September 2017

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.

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Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

September 2017

Volume

77

Issue

18

Start / End Page

5095 / 5106

Related Subject Headings

  • Tumor Cells, Cultured
  • Signal Transduction
  • Receptors, Peptide
  • Receptors, Guanylate Cyclase-Coupled
  • Receptors, Enterotoxin
  • Radiation Injuries, Experimental
  • Paracrine Communication
  • Oncology & Carcinogenesis
  • Natriuretic Peptides
  • Mice, Inbred C57BL
 

Citation

APA
Chicago
ICMJE
MLA
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Li, P., Wuthrick, E., Rappaport, J. A., Kraft, C., Lin, J. E., Marszalowicz, G., … Waldman, S. A. (2017). GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome. Cancer Research, 77(18), 5095–5106. https://doi.org/10.1158/0008-5472.can-17-0859
Li, Peng, Evan Wuthrick, Jeff A. Rappaport, Crystal Kraft, Jieru E. Lin, Glen Marszalowicz, Adam E. Snook, Tingting Zhan, Terry M. Hyslop, and Scott A. Waldman. “GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.Cancer Research 77, no. 18 (September 2017): 5095–5106. https://doi.org/10.1158/0008-5472.can-17-0859.
Li P, Wuthrick E, Rappaport JA, Kraft C, Lin JE, Marszalowicz G, et al. GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome. Cancer research. 2017 Sep;77(18):5095–106.
Li, Peng, et al. “GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome.Cancer Research, vol. 77, no. 18, Sept. 2017, pp. 5095–106. Epmc, doi:10.1158/0008-5472.can-17-0859.
Li P, Wuthrick E, Rappaport JA, Kraft C, Lin JE, Marszalowicz G, Snook AE, Zhan T, Hyslop TM, Waldman SA. GUCY2C Signaling Opposes the Acute Radiation-Induced GI Syndrome. Cancer research. 2017 Sep;77(18):5095–5106.

Published In

Cancer research

DOI

EISSN

1538-7445

ISSN

0008-5472

Publication Date

September 2017

Volume

77

Issue

18

Start / End Page

5095 / 5106

Related Subject Headings

  • Tumor Cells, Cultured
  • Signal Transduction
  • Receptors, Peptide
  • Receptors, Guanylate Cyclase-Coupled
  • Receptors, Enterotoxin
  • Radiation Injuries, Experimental
  • Paracrine Communication
  • Oncology & Carcinogenesis
  • Natriuretic Peptides
  • Mice, Inbred C57BL