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guanylyl cyclase C signaling axis and colon cancer prevention

World Journal of Gastroenterology 2016年第36期22卷 8070-8077页

作者： Amanda M Pattison Dante J Merlino Erik S Blomain Scott A Waldman Department of Pharmacology and Experimental Therapeutics Thomas Jefferson University

Colorectal cancer(CRC) is a major cause of cancerrelated mortality and morbidity worldwide. While improved treatments have enhanced overall patient outcome, disease burden encompassing quality of life, cost of care, and patient survival has seen little benefit. Consequently, additional advances in CRC treatments remain important, with an emphasis on preventative measures. guanylyl cyclase C(GUCY2C), a transmembrane receptor expressed on intestinal epithelial cells, plays an important role in orchestrating intestinal homeostatic mechanisms. These effects are mediated by the endogenous hormones guanylin(GUCA2A) and uroguanylin(GUCA2B), which bind and activate GUCY2 C to regulate proliferation, metabolism and barrier function in intestine. Recent studies have demonstrated a link between GUCY2 C silencing and intestinal dysfunction, including tumorigenesis. Indeed, GUCY2 C silencing by the near universal loss of its paracrine hormone ligands increases colon cancer susceptibility in animals and humans. GUCY2C's role as a tumor suppressor has opened the door to a new paradigm for CRC prevention by hormone replacement therapy using synthetic hormone analogs, such as the FDA-approved oral GUCY2 C ligand linaclotide(Linzess^(TM)). Here we review the known contributions of the GUCY2 C signaling axis to CRC, and relate them to a novel clinical strategy targeting tumor chemoprevention.

关键词： Colorectal cancer Guanylin Uroguanylin Chemoprevention Heat-stable enterotoxins Cyclic guanosine monophosphate guanylyl cyclase C

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Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models

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World Journal of Gastroenterology 2018年第17期24卷 1888-1900页

作者： Illona-Marie Boulete Anusha Thadi Catherine Beaufrand Viren Patwa Apoorva Joshi John A Foss E Priya Eddy Helene Eutamene Vaseem A Palejwala Vassilia Theodorou Kunwar Shailubhai UMR 1331 Toxalim INRA/INPT Toulouse 31555France Baruch S.Blumberg Institute DoylestownPA 18902United States Synergy Pharmaceuticals Inc. 420 Lexington AvenueNew YorkNY 10170United States

AIM To investigate the effects of plecanatide and dolcanatide on maintenance of paracellular permeability, integrity of tight junctions and on suppression of visceral hypersensitivity. METHODS Transport of fluorescein isothiocyanate(FITC)-dextran was measured to assess permeability across cell monolayers and rat colon tissues. Effects of plecanatide and dolcanatide on the integrity of tight junctions in Caco-2 and T84 monolayers and on the expression and localization of occludin and zonula occludens-1(ZO-1) were examined by immunofluorescence microscopy. Anti-nociceptive activity of these agonists was evaluated in trinitrobenzene sulfonic acid(TNBS)-induced inflammatory as well as in non-inflammatory partial restraint stress(PRS) rat models. Statistical significance between the treatment groups in the permeability studies were evaluated using unpaired *** Treatment of T84 and Caco-2 monolayers with lipopolysaccharide(LPS) rapidly increased permeability, which was effectively suppressed when monolayers were also treated with plecanatide or dolcanatide. Similarly, when T84 and Caco-2 monolayers were treated with LPS, cell surface localization of tight junction proteins occludin and ZO-1 was severely disrupted. When cell monolayers were treated with LPS in the presence of plecanatide or dolcanatide, occludin and ZO-1 were localized at the cell surface of adjoining cells, similar to that observed for vehicle treated cells. Treatment of cell monolayers with plecanatide or dolcanatide without LPS did not alter permeability, integrity of tight junctions and cell surface localization of either of the tight junction proteins. In rat visceral hypersensitivity models, both agonists suppressed the TNBS-induced increase in abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity, and both agonists also reduced colonic hypersensitivity in the PRS model. CONCLUSION Our results suggest that activation of GC-C signaling mi

关键词： Plecanatide guanylyl cyclase-C agonists Dolcanatide Uroguanylin Preclinical cyclic guanosine monophosphate Constipation Inflammatory bowel diseases

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PL-1 Cyclic Nucleotides Coordinates Cellular Function by Altering Phosphorylation of not One but Many Different Proteins in the Cell at the Same Time

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神经药理学报 2018年第4期8卷 13-14页

作者： Joseph Beavo University of Washington Seattle SeattleWA 98l95-7280USA

The levels of the second messenger cyclic nucleotides,cAMP and cGMP are carefully regulated in all cells by the activity of a series of adenylyl and guanylyl cyclases and cyclic nucleotide phosphodiesterases(PDEs).Most of the functions of these second messengers are mediated by activation of cyclic nucleotide dependent kinases or other discrete cyclic nucleotide binding ***,the regulation and function of all of these enzymes are greatly influenced by the cellular and subcellular compartments in which they are *** this talk I will discuss several examples of cAMP-regulated cellular function that depend on the simultaneous,coordinated phosphorylation of multiple control points as determined by phosphoproteomic analysis of cells treated with and without selective phosphodiesterase *** data strongly suggest that multiple PDEs work in a synergistic manner to coordinate different functional pools of *** different pools in turn coordinate not one,but many different steps to yield the final control of cellular *** data imply that we likely therefore will need to consider a number of new and revised ways to think about cAMP regulation of cellular functions and also about drug *** example,several different PDEs may need to be inhibited in order to produce meaningful pharmacological *** data also imply that the much of this cAMP regulation occurs as stochastic processes in different compartments in the cell.

关键词： adenylyl and guanylyl cyclases cAMP and cGMP

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