Guanylyl cyclase C agonists regulate progression through the cell cycle of human colon carcinoma cells

Pitari, Giovanni M.; Guglielmo, Matthew D. Di; Park, Jason; Schulz, Stephanie

doi:10.1073/pnas.141124698

Cited by 147 publications

(215 citation statements)

References 44 publications

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“…In addition, proliferation of glomerular mesangial cells by phorbol 12,13-dibutyrate-mediated activation of mitogen-activated protein kinase is antagonized by cGMPinduced expression of the specific phosphatase MKP-1 (27). Further, in colorectal cancer cells, the antiproliferative effects of cGMP may reflect activation of apoptotic pathways (28,29) or regulation of cell cycle (15). Conversely, cGMP-dependent activation of PKG promotes human umbilical vein endothelial cell proliferation by stimulating Raf-1 kinase activity (30).…”

Section: Resultsmentioning

confidence: 99%

“…The precise mode of Ca 2ϩ delivery to its intracellular site of action to induce intestinal cell cytostasis remains undefined. Yet, this antiproliferative process must be tightly regulated because Ca 2ϩ can, upon intracellular accumulation, promote apoptosis (42), which is not induced by ST (15).…”

Section: Resultsmentioning

confidence: 99%

“…Exponentially growing cancer cells (Ϸ60% confluent in 96-well plates) were synchronized by serum starvation in Eagle's minimal essential medium (EMEM) for 48 h, followed by proliferative induction with 10 mM L-glutamine (in EMEM) for 24 h. ST and other agents were added to cells 15 min before 0.2 Ci per well (1 Ci ϭ 37 GBq) of [methyl-3 H]thymidine, which was added for 3 h, followed by quantification of [ 3 H]thymidine incorporation into DNA (15).…”

Section: Methodsmentioning

confidence: 99%

“…Beyond volume homeostasis, GC-C and its ligands have been implicated in the regulation of the balance of proliferation and differentiation along the crypt-to-villus axis in the intestine (15).…”

mentioning

confidence: 99%

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Bacterial enterotoxins are associated with resistance to colon cancer

Pitari

Zingman

Hodgson

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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138

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One half million patients suffer from colorectal cancer in industrialized nations, yet this disease exhibits a low incidence in underdeveloped countries. This geographic imbalance suggests an environmental contribution to the resistance of endemic populations to intestinal neoplasia. A common epidemiological characteristic of these colon cancer-spared regions is the prevalence of enterotoxigenic bacteria associated with diarrheal disease. Here, a bacterial heat-stable enterotoxin was demonstrated to suppress colon cancer cell proliferation by a guanylyl cyclase C-mediated signaling cascade. The heat-stable enterotoxin suppressed proliferation by increasing intracellular cGMP, an effect mimicked by the cellpermeant analog 8-br-cGMP. The antiproliferative effects of the enterotoxin and 8-br-cGMP were reversed by L-cis-diltiazem, a cyclic nucleotide-gated channel inhibitor, as well as by removal of extracellular Ca 2؉ , or chelation of intracellular Ca 2؉ . In fact, both the enterotoxin and 8-br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca 2؉ influx and inhibition of DNA synthesis in colon cancer cells. Induction of this previously unrecognized antiproliferative signaling pathway by bacterial enterotoxin could contribute to the resistance of endemic populations to intestinal neoplasia, and offers a paradigm for targeted prevention and therapy of primary and metastatic colorectal cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Bacterial enterotoxins are associated with resistance to colon cancer

Pitari

Zingman

Hodgson

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

138

220

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“…Addition of exogenous uroguanylin 1 or guanylin, 4 mammalian ligands of GC-C, causes apoptosis in confluent T84 cells. A third study 5 showed that serum-stimulated proliferation was inhibited by ST or uroguanylin via a delay in cell cycle progression in the absence of apoptosis. It has recently been shown that ST exposure activates calcium influx through cyclic nucleotide-gated channels in rat colonocytes 6 and in T84 cells, where it is associated with decreased proliferation.…”

mentioning

confidence: 99%

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

Mann

Steinbrecher

Stroup

et al. 2005

Intl Journal of Cancer

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Guanylyl cyclase C (GC-C), a transmembrane receptor for bacterial heat-stable enterotoxin and the mammalian peptides guanylin and uroguanylin, mediates intestinal ion secretion and affects intestinal cell growth via cyclic GMP signaling. In intestinal tumors, GC-C expression is maintained while guanylin and uroguanylin expression is lost, suggesting a role for GC-C activation in tumor formation or growth. We show by in situ hybridization that GC-C expression is retained in adenomas from multiple intestinal neoplasia (Apc Min/+ ) mice. In order to determine the in vivo role of GC-C in intestinal tumorigenesis, we generated Apc Min/+ mice homozygous for a targeted deletion of the gene encoding GC-C and hypothesized that these mice would have increased tumor multiplicity and size compared to wild-type Apc Min/+ mice on the same genetic background. In contrast, the absence of GC-C resulted in a reduction of median polyp number by 55%. There was no change in the median diameter of polyps, suggesting no effect on tumor growth. Somatic loss of the wild-type Apc allele, an initiating event in intestinal tumorigenesis, also occurred in polyps from GC-C-deficient Apc Min/+ mice. We have found increased levels of apoptosis as well as increased caspase-3 and caspase-7 gene expression in the intestines of GC-C-deficient Apc Min/+ mice compared with Apc Min/+ mice. We propose that these alterations are a possible compensatory mechanism by which loss of GC-C signaling also affects tumorigenesis. Published 2005 Wiley-Liss, Inc.

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Incidence of periprocedural myocardial infarction following stent implantation: Comparison between first‐ and second‐generation drug‐eluting stents

Tandjung¹,

Basalus²,

Muurman³

et al. 2011

Cathet Cardio Intervent

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Guanylyl cyclase C agonists regulate progression through the cell cycle of human colon carcinoma cells

Abstract: The effects of Escherichia coli heat-stable enterotoxin (ST) and uroguanylin were examined on the proliferation of T84 and Caco2 human colon carcinoma cells that express guanylyl cyclase C (GC-C) and SW480 human colon carcinoma cells that do not express this receptor. ST

Cited by 147 publications

References 44 publications

Bacterial enterotoxins are associated with resistance to colon cancer

Bacterial enterotoxins are associated with resistance to colon cancer

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

Incidence of periprocedural myocardial infarction following stent implantation: Comparison between first‐ and second‐generation drug‐eluting stents

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