1521-0111/90/3/199–204$25.00 http://dx.doi.org/10.1124/mol.115.103192 MOLECULAR PHARMACOLOGY Mol Pharmacol 90:199–204, September 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics MINIREVIEW 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 Downloaded from Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania Received December 29, 2015; accepted May 25, 2016 ABSTRACT Obesity has emerged as a principal cause of mortality worldwide, in mice and humans. Hormone loss reflects reversible calorie- molpharm.aspetjournals.org reflecting comorbidities including cancer risk, particularly in induced endoplasmic reticulum stress and the associated colorectum. Although this relationship is established epidemio- unfolded protein response, rather than the endocrine, adipo- logically, molecular mechanisms linking colorectal cancer and kine, or inflammatory milieu of obesity. Loss of intestinal obesity continue to be refined. Guanylyl cyclase C (GUCY2C), uroguanylin secretion silences the hypothalamic GUCY2C a membrane-bound guanylyl cyclase expressed in intestinal endocrine axis, creating a feed-forward loop contributing to epithelial cells, binds the paracrine hormones guanylin and hyperphagia in obesity. Importantly, calorie-induced guanylin uroguanylin, inducing cGMP signaling in colorectum and small loss silences the GUCY2C-cGMP paracrine axis underlying intestine, respectively. Guanylin is the most commonly lost obesity-induced epithelial dysfunction and colorectal tumor- gene product in sporadic colorectal cancer, and its universal igenesis. Indeed, genetically enforced guanylin replacement loss early in transformation silences GUCY2C, a tumor sup- eliminated diet-induced intestinal tumorigenesis in mice. at ASPET Journals on September 25, 2021 pressor, disrupting epithelial homeostasis underlying tumori- Taken together, these observations suggest that GUCY2C genesis. In small intestine, eating induces endocrine secretion hormone axes are at the intersection of obesity and colorectal of uroguanylin, the afferent limb of a novel gut-brain axis that cancer. Moreover, they suggest that hormone replacement activates hypothalamic GUCY2C-cGMP signaling mediating that restores GUCY2C signaling may be a novel therapeutic satiety opposing obesity. Recent studies revealed that diet- paradigm to prevent both hyperphagia and intestinal tumor- induced obesity suppressed guanylin and uroguanylin expression igenesis in obesity. Introduction of endogenous mechanisms of metabolic regulation. Despite these insights, the molecular mechanisms that underlie Obesity is poised to become the leading cause of morbidity aberrant energy balance and feeding behavior in obesity, as and mortality in the United States and world (Yang and well as effective therapeutic strategies to combat these defects, Colditz, 2015). Two-thirds of the US adult population is remain elusive. 2 overweight [body mass index (BMI) 25 kg/m ], and half of Obesity is associated with comorbidities that reduce life . 2 that overweight population is obese (BMI 30 kg/m ) (Yang expectancy and incur substantial treatment costs, including and Colditz, 2015; Nagendran et al., 2016). This pandemic cancer, depression, diabetes, cardiovascular disease, hyper- reflects the convergence of reinforcing lifestyle issues, in- tension, infertility, liver disease, sleep apnea, osteoarthritis, cluding decreased energy demands coupled with increased and stroke (Astrup et al., 2015). Mechanistic relationships accessibility to calorie-dense foods, resulting in dysregulation that underlie some comorbidities, such as that between obesity and cardiovascular disease, are well characterized. This work was supported by the National Institutes of Health National In contrast, molecular mechanisms linking obesity to cancer Cancer Institute [Grants CA170533 and CA180500]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases continue to be refined. [Grant DK103492-01A1]; a Pharmaceutical Research and Manufacturers of This review highlights recent insights that causally link America Foundation Predoctoral Fellowship Award in Pharmacology; and the pathophysiology of overfeeding in obesity with mecha- Targeted Diagnostic and Therapeutics. Conflict of interest: S.A.W. is the Chair (uncompensated) of the Scientific nisms underlying colorectal tumorigenesis through guanylyl Advisory Board of Targeted Diagnostics & Therapeutics, which provided cyclase C (GUCY2C)-hormone signaling axes. This emerging research funding that, in part, supported this work and has a license to commercialize inventions related to this work. pathophysiological paradigm suggests that consumption of dx.doi.org/10.1124/mol.115.103192. excess calories suppresses GUCY2C hormone expression in ABBREVIATIONS: BMI, body mass index; ER, endoplasmic reticulum; GUCY2C, guanylyl cyclase C; ST, bacterial heat-stable enterotoxin. 199 200 Blomain et al. intestine, disrupting hypothalamic endocrine regulation of recapitulates discreet attributes of tumorigenesis, including satiety promoting hyperphagia and paracrine regulation of an expanded proliferating crypt compartment, increased DNA colorectal epithelial homeostasis underlying tumorigenesis. damage, metabolic reprogramming to a Warburg glycolytic The correlative therapeutic paradigm suggests that hyper- phenotype, restricted differentiation and lineage commit- phagia and colorectal cancer contributing to the morbidity of ment, and amplified oncogenic signaling through changes in obesity both can be prevented by hormone replacement that p21, Akt, and other pathways (Li et al., 2007b; Rinaldi et al., restores GUCY2C signaling. 2010; Han et al., 2011; Okabayashi et al., 2012). Consistent with its role as a tumor suppressor, intestinal neoplasia in Gucy2c2/2 mice was substantially increased, compared with GUCY2C Signaling and the Paracrine Hormone wild-type mice, by the chemical carcinogen azoxymethane or Hypothesis of Colorectal Cancer by mutations in adenomatous polyposis coli (Li et al., 2007b; Rinaldi et al., 2010; Basu et al., 2014). GUCY2C is a membrane-associated guanylyl cyclase re- The GUCY2C paracrine hormones guanylin and uroguanylin ceptor expressed primarily in intestinal epithelium (Kuhn, are the most commonly lost gene products in colorectal cancer 2016) and in brain (Gong et al., 2011; Valentino et al., 2011; (Zhang et al., 1997; Cohen et al., 1998; Steinbrecher et al., Begg et al., 2014; Kim et al., 2016). Cognate ligands are 2000; Notterman et al., 2001), and this loss produces epithelial Downloaded from structurally similar peptides and include the hormones dysfunction recapitulating the phenotype in Gucy2c2/2 mice. guanylin and uroguanylin produced in small and large in- In preliminary studies, guanylin mRNA was lost early in the testine, respectively, and the bacterial heat-stable entero- pathophysiological continuum of tumorigenesis, and adeno- toxins (STs) produced by diarrheagenic bacteria (Canani et al., mas, as well as adenocarcinomas, were devoid of guanylin 2015; Kuhn, 2016). In intestine, GUCY2C resides in apical expression in both mice and humans (Zhang et al., 1997; brush border membranes, where it has a role in fluid Cohen et al., 1998; Steinbrecher et al., 2000; Notterman et al., homeostasis. Indeed, one of the best-characterized functions 2001). In a cohort of ∼300 human patients, guanylin mRNA molpharm.aspetjournals.org of GUCY2C is driving intestinal secretion and ST-induced and protein were lost by .85% of colorectal tumors compared enterotoxigenic diarrhea (Fiskerstrand et al., 2012; Kuhn, with matched normal adjacent tissue (Wilson et al., 2014). 2016). Association of ST with the extracellular ligand binding Together, these observations reveal that guanylin loss silenc- domain of GUCY2C activates the cytoplasmic catalytic do- ing GUCY2C is a universal mechanism that occurs at the main, which converts GTP to cGMP. In small intestine, this earliest stages of transformation through a process that is second messenger activates cGMP-dependent protein kinase conserved across species. In turn, they suggest that guanylin PKGII (Vaandrager et al., 2000). In contrast, in colorectum loss silencing the GUCY2C tumor suppressor plays a funda- cGMP inhibits phosphodiesterase type 3, raising intracellular mental role in the pathogenesis of colorectal cancer initiation. concentrations of cAMP (Chao et al., 1994; Poppe et al., 2008). The ability to translate these findings to effective cancer at ASPET Journals on September 25, 2021 These signaling events lead to phosphorylation of the cystic prevention is underscored by the approval of the oral fibrosis transmembrane conductance regulator, a chloride GUCY2C ligand linaclotide (Linzess)(IronwoodPharmaceu- channel, which mediates the concentration-dependent efflux ticals, Cambridge, MA) to treat constipation-type irritable of chloride and bicarbonate ions from intestinal cells bowel syndrome and chronic constipation, using a clinically (Fiskerstrand et al., 2012; Dekkers et al., 2013; Kuhn, 2016). tractable paradigm to reactivate the dormant paracrine This flow of anions drives electrogenic sodium efflux, pro- GUCY2C-cGMP signaling axis to prevent intestinal tumor- ducing an osmotic gradient that ultimately results in fluid igenesis (Brenner, 2013; Scarpignato and Blandizzi, 2014).