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Muscarinic Receptor Signaling in Colon Cancer
University of Maryland School of Medicine, Division of Gastroenterology & Hepatology, 22 S. Greene Street, N3W62, Baltimore, MD 21201, USA
Department of Veterans Affairs, VA Maryland Health Care System, 10 North Greene Street, Baltimore, MD 21201, USA
* Author to whom correspondence should be addressed.
Received: 31 January 2011; in revised form: 14 February 2011 / Accepted: 24 February 2011 / Published: 2 March 2011
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.
Keywords: colon cancer; bile acids; muscarinic receptors; epidermal growth factor receptors
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Von Rosenvinge, E.C.; Raufman, J.-P. Muscarinic Receptor Signaling in Colon Cancer. Cancers 2011, 3, 971-981.
Von Rosenvinge EC, Raufman J-P. Muscarinic Receptor Signaling in Colon Cancer. Cancers. 2011; 3(1):971-981.
Von Rosenvinge, Erik C.; Raufman, Jean-Pierre. 2011. "Muscarinic Receptor Signaling in Colon Cancer." Cancers 3, no. 1: 971-981.