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Molecular Pharmacology

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Rapid CommunicationMinireview

Guanylyl Cyclase C Hormone Axis at the Intersection of Obesity and Colorectal Cancer

Erik S. Blomain, Dante J. Merlino, Amanda M. Pattison, Adam E. Snook and Scott A. Waldman
Molecular Pharmacology September 2016, 90 (3) 199-204; DOI: https://doi.org/10.1124/mol.115.103192
Erik S. Blomain
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania
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Dante J. Merlino
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania
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Amanda M. Pattison
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania
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Adam E. Snook
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania
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Scott A. Waldman
Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania
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Abstract

Obesity has emerged as a principal cause of mortality worldwide, reflecting comorbidities including cancer risk, particularly in colorectum. Although this relationship is established epidemiologically, molecular mechanisms linking colorectal cancer and obesity continue to be refined. Guanylyl cyclase C (GUCY2C), a membrane-bound guanylyl cyclase expressed in intestinal epithelial cells, binds the paracrine hormones guanylin and uroguanylin, inducing cGMP signaling in colorectum and small intestine, respectively. Guanylin is the most commonly lost gene product in sporadic colorectal cancer, and its universal loss early in transformation silences GUCY2C, a tumor suppressor, disrupting epithelial homeostasis underlying tumorigenesis. In small intestine, eating induces endocrine secretion of uroguanylin, the afferent limb of a novel gut-brain axis that activates hypothalamic GUCY2C-cGMP signaling mediating satiety opposing obesity. Recent studies revealed that diet-induced obesity suppressed guanylin and uroguanylin expression in mice and humans. Hormone loss reflects reversible calorie-induced endoplasmic reticulum stress and the associated unfolded protein response, rather than the endocrine, adipokine, or inflammatory milieu of obesity. Loss of intestinal uroguanylin secretion silences the hypothalamic GUCY2C endocrine axis, creating a feed-forward loop contributing to hyperphagia in obesity. Importantly, calorie-induced guanylin loss silences the GUCY2C-cGMP paracrine axis underlying obesity-induced epithelial dysfunction and colorectal tumorigenesis. Indeed, genetically enforced guanylin replacement eliminated diet-induced intestinal tumorigenesis in mice. Taken together, these observations suggest that GUCY2C hormone axes are at the intersection of obesity and colorectal cancer. Moreover, they suggest that hormone replacement that restores GUCY2C signaling may be a novel therapeutic paradigm to prevent both hyperphagia and intestinal tumorigenesis in obesity.

Footnotes

    • Received December 29, 2015.
    • Accepted May 25, 2016.
  • This work was supported by the National Institutes of Health National Cancer Institute [Grants CA170533 and CA180500]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK103492-01A1]; a Pharmaceutical Research and Manufacturers of America Foundation Predoctoral Fellowship Award in Pharmacology; and Targeted Diagnostic and Therapeutics.

  • Conflict of interest: S.A.W. is the Chair (uncompensated) of the Scientific Advisory Board of Targeted Diagnostics & Therapeutics, which provided research funding that, in part, supported this work and has a license to commercialize inventions related to this work.

  • dx.doi.org/10.1124/mol.115.103192.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 90 (3)
Molecular Pharmacology
Vol. 90, Issue 3
1 Sep 2016
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Rapid CommunicationMinireview

GUCY2C, Obesity, and Colorectal Cancer

Erik S. Blomain, Dante J. Merlino, Amanda M. Pattison, Adam E. Snook and Scott A. Waldman
Molecular Pharmacology September 1, 2016, 90 (3) 199-204; DOI: https://doi.org/10.1124/mol.115.103192

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Rapid CommunicationMinireview

GUCY2C, Obesity, and Colorectal Cancer

Erik S. Blomain, Dante J. Merlino, Amanda M. Pattison, Adam E. Snook and Scott A. Waldman
Molecular Pharmacology September 1, 2016, 90 (3) 199-204; DOI: https://doi.org/10.1124/mol.115.103192
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  • Article
    • Abstract
    • Introduction
    • GUCY2C Signaling and the Paracrine Hormone Hypothesis of Colorectal Cancer
    • The GUCY2C Endocrine Hormone Axis in Appetite and Satiety
    • Diet-Induced Suppression of GUCY2C Hormones and the Pathophysiology of Obesity
    • GUCY2C and Obesity-Associated Colorectal Cancer
    • Obesity Silences the GUCY2C Paracrine Axis, Leading to Tumorigenesis
    • Endoplasmic Reticulum Stress Suppresses GUCY2C Hormone Expression in Diet-Induced Obesity
    • Translation of GUCY2C-Targeted Chemoprevention for Colorectal Cancer
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