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.
Highlights
Each year, ~150,000 people in the United States are diagnosed with colon cancer, the leading gastrointestinal (GI) cause of death [1]
In the course of examining actions of bile acids on pepsinogen secretion by gastric chief cells we found that taurine conjugates of lithocholic acid bind to muscarinic receptors, increase inositol phosphates (IP), and stimulate secretion by a cholinergic mechanism [8]
Using q-PCR, immunohistochemistry and ELISA, we showed that H508 colon cancer cells express matrix metalloproteinase-7 (MMP7) and that MMP7 gene transcription is induced by bile acids
Summary
Each year, ~150,000 people in the United States are diagnosed with colon cancer (http://www.cancer.org/), the leading gastrointestinal (GI) cause of death [1]. Novel chemotherapeutic agents and treatments that target the ligand-binding and kinase domains of epidermal growth factor receptors have provided limited improvement in survival. In rodent cancer models, increased fecal bile acids promote colon dysplasia [4]. CHRM3 are expressed widely in the GI tract and in colon cancer cells [11]; in one small study, compared to adjacent normal tissue, in 63% of colon cancer specimens CHRM3 expression was increased up to 8-fold [12]. These observations identify elements of muscarinic receptor signaling as novel targets to prevent and treat colon neoplasia
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