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1.
Cancer Res ; 76(2): 339-46, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26773096

RESUMO

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.


Assuntos
Neoplasias Colorretais/metabolismo , Hormônios Gastrointestinais/metabolismo , Peptídeos Natriuréticos/metabolismo , Obesidade/metabolismo , Receptores Acoplados a Guanilato Ciclase/metabolismo , Receptores de Peptídeos/metabolismo , Animais , Células CACO-2 , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Genótipo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/patologia , Comunicação Parácrina , Receptores de Enterotoxina , Fatores de Risco , Transdução de Sinais
2.
Cancer Res ; 73(22): 6654-66, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24085786

RESUMO

Tumorigenesis is a multistep process that reflects intimate reciprocal interactions between epithelia and underlying stroma. However, tumor-initiating mechanisms coordinating transformation of both epithelial and stromal components are not defined. In humans and mice, initiation of colorectal cancer is universally associated with loss of guanylin and uroguanylin, the endogenous ligands for the tumor suppressor guanylyl cyclase C (GUCY2C), disrupting a network of homeostatic mechanisms along the crypt-surface axis. Here, we reveal that silencing GUCY2C in human colon cancer cells increases Akt-dependent TGF-ß secretion, activating fibroblasts through TGF-ß type I receptors and Smad3 phosphorylation. In turn, activating TGF-ß signaling induces fibroblasts to secrete hepatocyte growth factor (HGF), reciprocally driving colon cancer cell proliferation through cMET-dependent signaling. Elimination of GUCY2C signaling in mice (Gucy2c(-/-)) produces intestinal desmoplasia, with increased reactive myofibroblasts, which is suppressed by anti-TGF-ß antibodies or genetic silencing of Akt. Thus, GUCY2C coordinates intestinal epithelial-mesenchymal homeostasis through reciprocal paracrine circuits mediated by TGF-ß and HGF. In that context, GUCY2C signaling constitutes a direct link between the initiation of colorectal cancer and the induction of its associated desmoplastic stromal niche. The recent regulatory approval of oral GUCY2C ligands to treat chronic gastrointestinal disorders underscores the potential therapeutic opportunity for oral GUCY2C hormone replacement to prevent remodeling of the microenvironment essential for colorectal tumorigenesis.


Assuntos
Proliferação de Células , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/patologia , Intestinos/patologia , Receptores Acoplados a Guanilato Ciclase/fisiologia , Receptores de Peptídeos/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Células CACO-2 , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação para Baixo , Transição Epitelial-Mesenquimal/genética , Fibrose , Células HCT116 , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Enterotoxina , Nicho de Células-Tronco/genética
3.
Expert Opin Drug Discov ; 8(6): 655-71, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23621300

RESUMO

INTRODUCTION: Obesity is a worldwide pandemic. Obesity-related health and economic costs are staggering. Existing strategies to combat obesity through lifestyle improvements and medical intervention have had limited success. Pharmacotherapy, in combination with lifestyle modification, may play a vital role in reversing the disease burden. However, past and current weight-loss medications have had serious safety risks, notably cardiovascular and psychiatric events. AREAS COVERED: The authors review the strategies for designing new anti-obesity drugs by describing those currently in development. They describe their target, mechanism of action and developmental or regulatory status. Furthermore, they discuss the problem of weight regain following weight loss, and its relevance to the long-term success of anti-obesity pharmacotherapy. EXPERT OPINION: For weight management drugs to achieve the safety and efficacy required to be impactful, current studies are uncovering and characterizing new targets, including new signaling circuits and hormones regulating appetite and metabolism, and re-evaluating the role of pharmacotherapy in weight management. To avoid the safety failures of many past weight-loss drugs, the models and strategies covered in this article incorporate recent advances in knowledge and technology. We discuss the emergence of cGMP signaling as a potentially transformative target in weight management. Modulating cGMP signaling may represent an ideal goal for an anti-obesity pharmacotherapy, reflecting some of the major themes described in the present review: targeting pathways that are newly realized as relevant for weight management; promoting safety by re-purposing drugs that are safe, proven, and approved for clinical use; and having a synergistic effect on multiple, reinforcing pathways.


Assuntos
Fármacos Antiobesidade/farmacologia , Depressores do Apetite/farmacologia , GMP Cíclico/metabolismo , Obesidade/tratamento farmacológico , Aumento de Peso/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos , Fármacos Antiobesidade/uso terapêutico , Depressores do Apetite/uso terapêutico , Desenho de Fármacos , Humanos , Estilo de Vida , Modelos Teóricos
4.
Trends Endocrinol Metab ; 24(4): 165-73, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23375388

RESUMO

Guanylyl cyclase C (GUCY2C) has canonical centrality in defense of key intestinal homeostatic mechanisms, encompassing fluid and electrolyte balance, epithelial dynamics, antitumorigenesis, and intestinal barrier function. Recent discoveries expand the homeostatic role of GUCY2C to reveal a novel gut-brain endocrine axis regulating appetite, anchored by hypothalamic GUCY2C which is responsive to intestine-derived uroguanylin. Thus, GUCY2C may represent a new target for anti-obesity pharmacotherapy. Moreover, the coincident regulation of energy balance and tumor suppression by a single hormone receptor system suggests that the GUCY2C axis might contribute to the established relationship between obesity and colorectal cancer. This confluence suggests that hormone supplementation to reconstitute GUCY2C signaling may be an elegant strategy to reverse both pathophysiologic processes.


Assuntos
Neoplasias/metabolismo , Obesidade/metabolismo , Receptores Acoplados a Guanilato Ciclase/metabolismo , Receptores de Peptídeos/metabolismo , Humanos , Neoplasias/genética , Obesidade/genética , Receptores de Enterotoxina , Receptores Acoplados a Guanilato Ciclase/genética , Receptores de Peptídeos/genética
5.
Mol Aspects Med ; 34(1): 71-83, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23103610

RESUMO

The increase in obesity in the Unites States and around the world in the last decade is overwhelming. The number of overweight adults in the world surpassed 1 billion in 2008. Health hazards associated with obesity are serious and include heart disease, sleep apnea, diabetes, and cancer. Although lifestyle modifications are the most straightforward way to control weight, a large portion of the population may not be able to rely on this modality alone. Thus, the development of anti-obesity therapeutics represents a major unmet medical need. Historically, anti-obesity pharmacotherapies have been unsafe and minimally efficacious. A better understanding of the biology of appetite and metabolism provides an opportunity to develop drugs that may offer safer and more effective alternatives for weight management. This review discusses drugs that are currently on the market and in development as anti-obesity therapeutics based on their target and mechanism of action. It should serve as a roadmap to establish expectations for the near future for anti-obesity drug development.


Assuntos
Fármacos Antiobesidade/farmacologia , Obesidade/tratamento farmacológico , Apetite/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Humanos , Estilo de Vida , Lipase/antagonistas & inibidores , Lipase/metabolismo , Neuropeptídeos/metabolismo , Hormônios Pancreáticos/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Redução de Peso/efeitos dos fármacos
6.
J Clin Invest ; 121(9): 3578-88, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21865642

RESUMO

Intestinal enteroendocrine cells are critical to central regulation of caloric consumption, since they activate hypothalamic circuits that decrease appetite and thereby restrict meal size by secreting hormones in response to nutrients in the gut. Although guanylyl cyclase and downstream cGMP are essential regulators of centrally regulated feeding behavior in invertebrates, the role of this primordial signaling mechanism in mammalian appetite regulation has eluded definition. In intestinal epithelial cells, guanylyl cyclase 2C (GUCY2C) is a transmembrane receptor that makes cGMP in response to the paracrine hormones guanylin and uroguanylin, which regulate epithelial cell dynamics along the crypt-villus axis. Here, we show that silencing of GUCY2C in mice disrupts satiation, resulting in hyperphagia and subsequent obesity and metabolic syndrome. This defined an appetite-regulating uroguanylin-GUCY2C endocrine axis, which we confirmed by showing that nutrient intake induces intestinal prouroguanylin secretion into the circulation. The prohormone signal is selectively decoded in the hypothalamus by proteolytic liberation of uroguanylin, inducing GUCY2C signaling and consequent activation of downstream anorexigenic pathways. Thus, evolutionary diversification of primitive guanylyl cyclase signaling pathways allows GUCY2C to coordinate endocrine regulation of central food acquisition pathways with paracrine control of intestinal homeostasis. Moreover, the uroguanylin-GUCY2C endocrine axis may provide a therapeutic target to control appetite, obesity, and metabolic syndrome.


Assuntos
Comportamento Animal/fisiologia , Ingestão de Alimentos , Sistema Endócrino/metabolismo , Comportamento Alimentar/fisiologia , Peptídeos Natriuréticos/metabolismo , Receptores Acoplados a Guanilato Ciclase/metabolismo , Receptores de Peptídeos/metabolismo , Sistemas do Segundo Mensageiro/fisiologia , Animais , Composição Corporal , Peso Corporal , GMP Cíclico/metabolismo , Sistema Endócrino/citologia , Células Epiteliais/citologia , Células Epiteliais/imunologia , Feminino , Hipotálamo/metabolismo , Insulina/sangue , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos Natriuréticos/genética , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores de Enterotoxina , Receptores Acoplados a Guanilato Ciclase/genética , Receptores de Peptídeos/genética , Saciação
7.
Expert Rev Clin Pharmacol ; 4(2): 243-59, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21666781

RESUMO

Obesity has escalated into a pandemic over the past few decades. In turn, research efforts have sought to elucidate the molecular mechanisms underlying the regulation of energy balance. A host of endogenous mediators regulate appetite and metabolism, and thereby control both short- and long-term energy balance. These mediators, which include gut, pancreatic and adipose neuropeptides, have been targeted in the development of anti-obesity pharmacotherapy, with the goal of amplifying anorexigenic and lipolytic signaling or blocking orexigenic and lipogenic signaling. This article presents the efficacy and safety of these anti-obesity drugs.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Regulação do Apetite/efeitos dos fármacos , Regulação do Apetite/fisiologia , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/metabolismo , Fármacos Antiobesidade/farmacologia , Apetite/efeitos dos fármacos , Apetite/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Humanos , Obesidade/metabolismo , Resultado do Tratamento
8.
Circulation ; 117(11): 1378-87, 2008 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-18316484

RESUMO

BACKGROUND: A salient characteristic of dysfunctional myocardium progressing to heart failure is an upregulation of the adenylyl cyclase inhibitory guanine nucleotide (G) protein alpha subunit, G alpha(i2). It has not been determined conclusively whether increased Gi activity in the heart is beneficial or deleterious in vivo. Gi signaling has been implicated in the mechanism of cardioprotective agents; however, no in vivo evidence exists that any of the G alpha subunits are cardioprotective. We have created a novel molecular tool to specifically address the role of Gi proteins in normal and dysfunctional myocardium. METHODS AND RESULTS: We have developed a class-specific Gi inhibitor peptide, GiCT, composed of the region of G alpha(i2) that interacts specifically with G protein-coupled receptors. GiCT inhibits Gi signals specifically in vitro and in vivo, whereas Gs and Gq signals are not affected. In vivo expression of GiCT in transgenic mice effectively causes a "functional knockout" of cardiac G alpha(i2) signaling. Inducible, cardiac-specific GiCT transgenic mice display a baseline phenotype consistent with nontransgenic mice. However, when subjected to ischemia/reperfusion injury, GiCT transgenic mice demonstrate a significant increase in infarct size compared with nontransgenic mice (from 36.9+/-2.5% to 50.9+/-4.3%). Mechanistically, this post-ischemia/reperfusion phenotype includes increased myocardial apoptosis and resultant decreased contractile performance. CONCLUSIONS: Overall, our results demonstrate the in vivo utility of GiCT to dissect specific mechanisms attributed to Gi signaling in stressed myocardium. Our results with GiCT indicate that upregulation of G alpha(i2) is an adaptive protective response after ischemia to shield myocytes from apoptosis.


Assuntos
Apoptose/fisiologia , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/fisiologia , Mitocôndrias Cardíacas/fisiologia , Isquemia Miocárdica/fisiopatologia , Miócitos Cardíacos/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas/metabolismo , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/antagonistas & inibidores , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/química , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/genética , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Humanos , Isoproterenol/farmacologia , Camundongos , Camundongos Transgênicos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Estresse Oxidativo , Fragmentos de Peptídeos/genética , Ratos , Receptores Acoplados a Proteínas G/fisiologia , Proteínas Recombinantes de Fusão/fisiologia , Transdução de Sinais/fisiologia , Transdução Genética
9.
Arch Neurol ; 61(6): 926-8, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15210532

RESUMO

BACKGROUND: Mutations in CACNA1A, encoding a neuronal calcium channel subunit, and ATP1A2, encoding a catalytic subunit of a sodium-potassium-ATPase, have been found in some families with dominantly inherited hemiplegic migraine. OBJECTIVE: To determine the prevalence of mutations in these genes in individuals with different migraine syndromes. DESIGN: Prospective screening study. SETTING: University outpatient neurology clinic. Subjects Probands of 19 families with hemiplegic migraine, 7 with basilar migraine, 25 with migraine without aura, and 18 with migraine with aura, as well as 40 unaffected relatives of probands. INTERVENTIONS: All known exons and flanking introns of CACNA1A and ATP1A2 were subjected to denaturing high-performance liquid chromatography analysis of polymerase chain reaction-amplified genomic DNA. Exons with atypical elution patterns were sequenced by standard techniques. MAIN OUTCOME MEASURES: Presence of mutations in CACNA1A and ATP1A2. RESULTS: A single mutation (T666M) was found in CACNA1A in a patient with hemiplegic migraine and ataxia. No other mutation was identified in either gene. The frequency of a previously reported intronic insertion in ATP1A2 was not significantly different between patients with migraine and control subjects. CONCLUSION: These 2 genes are not associated with more common migraine syndromes and are not the most common hemiplegic migraine genes.


Assuntos
Canais de Cálcio/genética , Transtornos de Enxaqueca/genética , Mutação , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Adulto , Canais de Cálcio Tipo N , Canais de Cálcio Tipo P , Canais de Cálcio Tipo Q , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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