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Muscarinic receptor signaling in colon cancer.

Von Rosenvinge EC, Raufman JP - Cancers (Basel) (2011)

Bottom Line: Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia.In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors.In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

View Article: PubMed Central - PubMed

Affiliation: University of Maryland School of Medicine, Division of Gastroenterology & Hepatology, 22 S. Greene Street, N3W62, Baltimore, MD 21201, USA. evonrose@medicine.umaryland.edu.

ABSTRACT
According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

No MeSH data available.


Related in: MedlinePlus

Human bile acid metabolism. Human bile acids derive primarily from cholesterol metabolism in the liver. The 7α-hydroxylase enzyme is the rate-limiting step in the formation of 7-hydroxycholesterol, the precursor of cholic and chenodeoxycholic acid.
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f2-cancers-03-00971: Human bile acid metabolism. Human bile acids derive primarily from cholesterol metabolism in the liver. The 7α-hydroxylase enzyme is the rate-limiting step in the formation of 7-hydroxycholesterol, the precursor of cholic and chenodeoxycholic acid.

Mentions: Bile acids are produced by hepatocytes and secreted into bile, predominantly after conjugation (amidation) with taurine or glycine [40]. As illustrated in Figure 2, primary human bile acids derive from cholesterol metabolism following a series of steroid nucleus hydroxylations. These primary bile acids, cholic and chenodeoxycholic acids, are secreted into the small intestine where bacterial dehydroxylases, primarily from Clostridia species, modify these molecules to form the secondary bile acids, deoxycholic and lithocholic acids, respectively. Both primary and secondary bile acids are absorbed in the distal ileum by a highly efficient transporter on the apical surface of enterocytes (apical sodium-dependent bile acid transporter, commonly referred to as ASBT). Via the portal circulation, bile acids are transported back to the liver where secondary bile acids undergo conjugation (amidation) with either taurine or glycine, and are secreted into the biliary tree and intestines. Reduced expression or inactivation (mutation) of ASBT results in reduced bile acid up-take from the distal small intestine and increased fecal bile acids. The bile acid nuclear receptor Farnesoid X Receptor (FXR), a key regulator of bile acid homeostasis, is expressed widely in the GI tract. The actions of FXR and its possible role in colon cancer have recently been reviewed [41].


Muscarinic receptor signaling in colon cancer.

Von Rosenvinge EC, Raufman JP - Cancers (Basel) (2011)

Human bile acid metabolism. Human bile acids derive primarily from cholesterol metabolism in the liver. The 7α-hydroxylase enzyme is the rate-limiting step in the formation of 7-hydroxycholesterol, the precursor of cholic and chenodeoxycholic acid.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756399&req=5

f2-cancers-03-00971: Human bile acid metabolism. Human bile acids derive primarily from cholesterol metabolism in the liver. The 7α-hydroxylase enzyme is the rate-limiting step in the formation of 7-hydroxycholesterol, the precursor of cholic and chenodeoxycholic acid.
Mentions: Bile acids are produced by hepatocytes and secreted into bile, predominantly after conjugation (amidation) with taurine or glycine [40]. As illustrated in Figure 2, primary human bile acids derive from cholesterol metabolism following a series of steroid nucleus hydroxylations. These primary bile acids, cholic and chenodeoxycholic acids, are secreted into the small intestine where bacterial dehydroxylases, primarily from Clostridia species, modify these molecules to form the secondary bile acids, deoxycholic and lithocholic acids, respectively. Both primary and secondary bile acids are absorbed in the distal ileum by a highly efficient transporter on the apical surface of enterocytes (apical sodium-dependent bile acid transporter, commonly referred to as ASBT). Via the portal circulation, bile acids are transported back to the liver where secondary bile acids undergo conjugation (amidation) with either taurine or glycine, and are secreted into the biliary tree and intestines. Reduced expression or inactivation (mutation) of ASBT results in reduced bile acid up-take from the distal small intestine and increased fecal bile acids. The bile acid nuclear receptor Farnesoid X Receptor (FXR), a key regulator of bile acid homeostasis, is expressed widely in the GI tract. The actions of FXR and its possible role in colon cancer have recently been reviewed [41].

Bottom Line: Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia.In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors.In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

View Article: PubMed Central - PubMed

Affiliation: University of Maryland School of Medicine, Division of Gastroenterology & Hepatology, 22 S. Greene Street, N3W62, Baltimore, MD 21201, USA. evonrose@medicine.umaryland.edu.

ABSTRACT
According to the adenoma-carcinoma sequence, colon cancer results from accumulating somatic gene mutations; environmental growth factors accelerate and augment this process. For example, diets rich in meat and fat increase fecal bile acids and colon cancer risk. In rodent cancer models, increased fecal bile acids promote colon dysplasia. Conversely, in rodents and in persons with inflammatory bowel disease, low-dose ursodeoxycholic acid treatment alters fecal bile acid composition and attenuates colon neoplasia. In the course of elucidating the mechanism underlying these actions, we discovered that bile acids interact functionally with intestinal muscarinic receptors. The present communication reviews muscarinic receptor expression in normal and neoplastic colon epithelium, the role of autocrine signaling following synthesis and release of acetylcholine from colon cancer cells, post-muscarinic receptor signaling including the role of transactivation of epidermal growth factor receptors and activation of the ERK and PI3K/AKT signaling pathways, the structural biology and metabolism of bile acids and evidence for functional interaction of bile acids with muscarinic receptors on human colon cancer cells. In murine colon cancer models, deficiency of subtype 3 muscarinic receptors attenuates intestinal neoplasia; a proof-of-concept supporting muscarinic receptor signaling as a therapeutic target for colon cancer.

No MeSH data available.


Related in: MedlinePlus