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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

Tissue distribution and signal transduction pathways of the five muscarinic receptor subtypes.
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f1-cancers-03-00971: Tissue distribution and signal transduction pathways of the five muscarinic receptor subtypes.

Mentions: Muscarinic receptors are members of the large family of G-protein coupled receptors (GPCR) that activate 5′-phosphate (G) proteins. G-proteins regulate a wide-range of biological processes by modulating the activity of adenylyl cyclase, phosphatidylinositol lipid turnover and ion channels [13,14]. Like other G-protein coupled receptors, muscarinic receptors have seven transmembrane helical domains connected by three extracellular and three intracellular loops. Five receptor subtypes, CHRM1-5, identified by molecular cloning techniques, modulate cell function by different post-receptor signaling pathways (Figure 1) [15]. Activation of CHRM1, CHRM3 and CHRM5 results in phospholipid turnover and changes in cell calcium concentration. Activation of CHRM2 and CHRM4 results in inhibition of adenylyl cyclase and reduced levels of cAMP.


Muscarinic receptor signaling in colon cancer.

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

Tissue distribution and signal transduction pathways of the five muscarinic receptor subtypes.
© Copyright Policy
Related In: Results  -  Collection

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

f1-cancers-03-00971: Tissue distribution and signal transduction pathways of the five muscarinic receptor subtypes.
Mentions: Muscarinic receptors are members of the large family of G-protein coupled receptors (GPCR) that activate 5′-phosphate (G) proteins. G-proteins regulate a wide-range of biological processes by modulating the activity of adenylyl cyclase, phosphatidylinositol lipid turnover and ion channels [13,14]. Like other G-protein coupled receptors, muscarinic receptors have seven transmembrane helical domains connected by three extracellular and three intracellular loops. Five receptor subtypes, CHRM1-5, identified by molecular cloning techniques, modulate cell function by different post-receptor signaling pathways (Figure 1) [15]. Activation of CHRM1, CHRM3 and CHRM5 results in phospholipid turnover and changes in cell calcium concentration. Activation of CHRM2 and CHRM4 results in inhibition of adenylyl cyclase and reduced levels of cAMP.

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