The Hormone Receptor GUCY2C Suppresses Intestinal Tumor Formation by Inhibiting AKT Signaling

Lin, Jieru E.; Li, Peng; Snook, Adam E.; Schulz, Stephanie; Dasgupta, Abhijit; Hyslop, Terry; Gibbons, Ahmara Vivian; Marszlowicz, Glen; Pitari, Giovanni M.; Waldman, Scott A.

doi:10.1053/j.gastro.2009.08.064

Cited by 107 publications

(206 citation statements)

References 46 publications

(86 reference statements)

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“…Regulation of PTEN by cGMP/PKG2 signaling is likely because the total PTEN levels were affected by PKG2 expression and activation. These results are consistent with a previous study in HCT116 colon cancer cells, 29 but the precise relationship between PKG2 and PTEN has yet to be elucidated. PTEN activity plays an important role downstream of PKG2 because knockdown of PTEN expression blocked the inhibitory effect of PKG2 on phospho-AKT in colon cancer cells.…”

Section: Pkg2 Activates Foxo3a In the Colonsupporting

confidence: 83%

“…29 The results shown herein extend our understanding of this phenomenon by demonstrating that PKG2 mediates AKT inhibition downstream of cGMP in this pathway. Independent work has shown that PKG2 also suppresses AKT in gastric cancer cell lines, where the mechanism was suggested to occur at the level of receptortyrosine kinases because ERK was also inhibited.…”

Section: Pkg2 Activates Foxo3a In the Colonsupporting

confidence: 47%

“…21,29 Knockout mice that are deficient in cGMP signaling exhibit aberrant AKT activity in the colon mucosa that coincides with elevated epithelial proliferation within crypts. 21,22 Because AKT is an established promoter of proliferation and survival, this pathway may directly contribute to crypt hyperplasia in these knockout mice.…”

Section: Pkg2 Activates Foxo3a In the Colonmentioning

confidence: 99%

“…38 More recently, type 2 PKG (PKG2) has also been reported to inhibit proliferation in gastric cancer cells lines by a mechanism involving inhibition of extracellular signal regulated kinase (ERK) and AKT signaling pathways. 29,39,40 To determine whether PKG2 can also inhibit these pathways in colon cancer cells, we made use of cell lines made inducible for PKG2 expression that have been characterized previously. 26 Activation of PKG2 in LS174T colon cancer cells inhibited growth without affecting apoptosis ( Figure 1, A and B).…”

Section: Pkg2 Inhibits Akt Signaling and Proliferation In Colon Cancementioning

confidence: 99%

“…29 There are four mammalian FoxO proteins that are widely expressed, but with differences in isoform-specific expression in various tissues. FoxO 1, 3a, and 4 are ubiquitous but are at higher levels in adipose tissue, liver, and skeletal muscle (respectively), whereas FoxO6 is predominantly found in the brain.…”

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confidence: 99%

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cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

Wang

Islam

Bridges

et al. 2017

The American Journal of Pathology

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Signaling through cGMP has therapeutic potential in the colon, where it has been implicated in the suppression of colitis and colon cancer. In this study, we tested the ability of cGMP and type 2 cGMPdependent protein kinase (PKG2) to activate forkhead box O (FoxO) in colon cancer cells and in the colon epithelium of mice. We show that activation of PKG2 in colon cancer cells inhibited cell proliferation, inhibited AKT, and activated FoxO. Treatment of colon explants with 8Br-cGMP also activated FoxO target gene expression at both RNA and protein levels, and reduced epithelial reduction-oxidation (redox) stress. FoxO3a was the most prominent isoform in the distal colon epithelium, with prominent luminal staining. FoxO3a levels were reduced in Prkg2 À/À animals, and FoxO target genes were unaffected by 8Br-cGMP challenge in vitro. Treatment of mice with the phosphodiesterase-5 inhibitor vardenafil (Levitra) mobilized FoxO3a to the nucleus of luminal epithelial cells, which corresponded to increased FoxO target gene expression, reduced redox stress, and increased epithelial barrier integrity. Treatment of human colonic biopsy specimens with 8Br-cGMP also activated catalase and manganese superoxide dismutase expression, indicating that this pathway is conserved in humans. Taken together, these results identify a novel signaling pathway in the colon epithelium, where FoxO tumor suppressors could provide protection from redox stress. Moreover, this pathway is regulated by endogenous cGMP/PKG2 signaling, and can be targeted using phosphodiesterase-5 inhibitors. (Am J Pathol 2017, 187: 377e389; http://dx

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Section: Pkg2 Activates Foxo3a In the Colonsupporting

confidence: 83%

Section: Pkg2 Activates Foxo3a In the Colonsupporting

confidence: 47%

Section: Pkg2 Activates Foxo3a In the Colonmentioning

confidence: 99%

Section: Pkg2 Inhibits Akt Signaling and Proliferation In Colon Cancementioning

confidence: 99%

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confidence: 99%

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cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

Wang

Islam

Bridges

et al. 2017

The American Journal of Pathology

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Cyclic 3′,5′-guanosine monophosphate-dependent protein kinase inhibits colon cancer cell adaptation to hypoxia

Kwon

Wang

Prakash

et al. 2011

Cancer

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BACKGROUND: Type 1 cyclic 3 0 ,5 0 -guanosine monophosphate-dependent protein kinase (PKG) has recently been reported to inhibit tumor growth and angiogenesis. These effects suggest that PKG activation may have therapeutic value for colon cancer treatment, but the signaling downstream of this enzyme is poorly understood. The present study examined the mechanism underlying the inhibition of angiogenesis by PKG. METHODS: The effect of ectopically expressed PKG on colon cancer cell adaptation to a 1% O 2 (hypoxic) environment was examined in vitro by measuring hypoxic markers, cell death/viability, and hypoxia inducible factor (HIF) activity. RESULTS: Ectopic PKG inhibited angiogenesis in SW620 xenografts and significantly attenuated hypoxia-induced increases in vascular endothelial growth factor at both the mRNA and protein levels. PKG activation also blocked hypoxia-induced hexokinase 2 expression, which corresponded with reduced cellular adenosine triphosphate levels. Moreover, PKG expression significantly reduced cell viability and promoted necrotic cell death after 2 days in a hypoxic environment. To gain some mechanistic insight, the effect of PKG on HIF activation was determined using luciferase reporter assays. PKG activation inhibited HIF transcriptional activity in several colon cancer cell lines, including SW620, HCT116, and HT29. The mechanism by which PKG can inhibit HIF activity is not known, but it does not affect HIF-1a protein accumulation or nuclear translocation. CONCLUSIONS: These findings demonstrate for the first time that PKG can block the adaptation of colon cancer cells to hypoxia and highlights this enzyme for further evaluation as a potential target for colon cancer treatment. Cancer 2011;117:5282-93.

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Physiology of Electrolyte Transport in the Gut: Implications for Disease

Rao

2019

Comprehensive Physiology

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We now have an increased understanding of the genetics, cell biology, and physiology of electrolyte transport processes in the mammalian intestine, due to the availability of sophisticated methodologies ranging from genome wide association studies to CRISPR‐CAS technology, stem cell‐derived organoids, 3D microscopy, electron cryomicroscopy, single cell RNA sequencing, transgenic methodologies, and tools to manipulate cellular processes at a molecular level. This knowledge has simultaneously underscored the complexity of biological systems and the interdependence of multiple regulatory systems. In addition to the plethora of mammalian neurohumoral factors and their cross talk, advances in pyrosequencing and metagenomic analyses have highlighted the relevance of the microbiome to intestinal regulation. This article provides an overview of our current understanding of electrolyte transport processes in the small and large intestine, their regulation in health and how dysregulation at multiple levels can result in disease. Intestinal electrolyte transport is a balance of ion secretory and ion absorptive processes, all exquisitely dependent on the basolateral Na + /K + ATPase; when this balance goes awry, it can result in diarrhea or in constipation. The key transporters involved in secretion are the apical membrane Cl − channels and the basolateral Na + ‐K + ‐2Cl − cotransporter, NKCC1 and K + channels. Absorption chiefly involves apical membrane Na + /H + exchangers and Cl − /HCO 3 − exchangers in the small intestine and proximal colon and Na + channels in the distal colon. Key examples of our current understanding of infectious, inflammatory, and genetic diarrheal diseases and of constipation are provided. © 2019 American Physiological Society. Compr Physiol 9:947‐1023, 2019.

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The Hormone Receptor GUCY2C Suppresses Intestinal Tumor Formation by Inhibiting AKT Signaling

Abstract: Background & Aims-Gucy2c is the intestinal cell receptor for the paracrine hormones guanylin and uroguanylin that converts GTP to cyclic (c)GMP. It functions as a tumor suppressor; its loss

Cited by 107 publications

References 46 publications

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium

Cyclic 3′,5′-guanosine monophosphate-dependent protein kinase inhibits colon cancer cell adaptation to hypoxia

Physiology of Electrolyte Transport in the Gut: Implications for Disease

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