Abstract
BackgroundPreviously, we showed that M3 muscarinic receptor (M3R; gene name Chrm3) deficiency attenuates murine intestinal neoplasia, supporting the hypothesis that muscarinic receptors play an important role in intestinal tumorigenesis.MethodsTo test this hypothesis, in the present study we treated mice with bethanechol, a non-selective muscarinic receptor agonist without nicotinic receptor activity, and examined its effects on azoxymethane (AOM)-induced colon neoplasia. Mice were provided with drinking water containing 400 μg/mL bethanechol chloride or water without additions (control) for a total of 20 weeks, a period that included the initial 6 weeks when mice received intraperitoneal injections of AOM.ResultsWhen euthanized at week 20, control mice had 8.0 ± 1.3 tumors per animal, whereas bethanechol-treated mice had 10.4 ± 1.5 tumors per mouse (mean ± SE; P = 0.023), a 30% increase. Strikingly, tumor volume per animal was increased 52% in bethanechol-treated compared with control mice (179.7 ± 21.0 vs. 111. 8 ± 22.4 mm3; P = 0.047). On histological examination, bethenechol-treated mice also had more adenocarcinomas per animal (8.0 ± 1.0 vs. 4.1 ± 0.6 for control mice, P = 0.0042). Cell proliferation in both normal mucosa and adenocarcinomas was increased in bethanechol-treated compared to control mice. Also, in tumors, bethanechol treatment increased expression of Chrm3, Egfr and post-Egfr signaling molecules Myc and cyclin D1. Bethanechol treatment increased the thickness of normal colonic mucosa and the expression of selected matrix metalloproteinase (Mmp) genes, including Mmp7, Mmp10 and Mmp13.ConclusionsThese findings support a prominent role for muscarinic receptors in colon neoplasia, and identify post-receptor signaling molecules as potential therapeutic targets.
Highlights
We showed that M3 muscarinic receptor (M3R; gene name Chrm3) deficiency attenuates murine intestinal neoplasia, supporting the hypothesis that muscarinic receptors play an important role in intestinal tumorigenesis
Using human colon cancer cells that express high levels of M3R, we showed that muscarinic agonist-induced cell proliferation is mediated by cross-talk between M3R and epidermal growth factor receptors (EGFRs) and activation of post-EGFR signaling mediated by p44/42 mitogen-activated protein kinase (ERK) [6,7]
Bethanechol promotes colon tumor formation Previously, we showed that M3 muscarinic receptors (M3R) promote intestinal tumorigenesis in murine models of colon cancer [4,5]
Summary
We showed that M3 muscarinic receptor (M3R; gene name Chrm3) deficiency attenuates murine intestinal neoplasia, supporting the hypothesis that muscarinic receptors play an important role in intestinal tumorigenesis. The muscarinic cholinergic family of G protein-coupled receptors (GPCRs) consists of five subtypes designated M1R-M5R. Emerging evidence indicates that muscarinic receptors play an important role in colon cancer cell proliferation and tumorigenesis. Additional biological plausibility for the role of M3R was provided by work from our lab elucidating the molecular mechanisms underlying cholinergic agonist-induced colon neoplasia. Using human colon cancer cells that express high levels of M3R, we showed that muscarinic agonist-induced cell proliferation is mediated by cross-talk between M3R and epidermal growth factor receptors (EGFRs) and activation of post-EGFR signaling mediated by p44/42 mitogen-activated protein kinase (ERK) [6,7]. We showed that M3R activation stimulates robust expression of matrix metalloproteinase (MMP) genes, including MMP1, MMP7 and MMP10, which play key roles in mediating cell proliferation, cell migration and invasion in vitro [8,9,10]
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