期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 295, 期 3, 页码 G591-G597出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00055.2008
关键词
autocrine signaling; choline acetyltransferase; muscarinic receptors
资金
- Office of Research and Development, Medical Research Service, Department of Veterans Affairs
- NIH [CA- 107345]
- American Gastroenterological Association Institute Student Research
- University of Maryland School of Medicine [T32 DK- 067872]
Most colon cancers overexpress M-3 muscarinic receptors (M3R), and post-M3R signaling stimulates human colon cancer cell proliferation. Acetylcholine (ACh), a muscarinic receptor ligand traditionally regarded as a neurotransmitter, may be produced by nonneuronal cells. We hypothesized that ACh release by human colon cancer cells results in autocrine stimulation of proliferation. H508 human colon cancer cells, which have robust M3R expression, were used to examine effects of muscarinic receptor antagonists, acetylcholinesterase inhibitors, and choline transport inhibitors on cell proliferation. A nonselective muscarinic receptor antagonist (atropine), a selective M3R antagonist (p-fluorohexahydro-sila-difenidol hydrochloride), and a choline transport inhibitor (hemicholinum-3) all inhibited unstimulated H508 colon cancer cell proliferation by similar to 40% (P < 0.005). In contrast, two acetylcholinesterase inhibitors (eserine-hemisulfate and bis-9-amino1,2,3,4-tetrahydroacridine) increased proliferation by 2.5-and 2-fold, respectively (P < 0.005). By using quantitative real-time PCR, expression of choline acetyltransferase (ChAT), a critical enzyme for ACh synthesis, was identified in H508, WiDr, and Caco-2 colon cancer cells. By using high-performance liquid chromatography-electrochemical detection, released ACh was detected in H508 and Caco-2 cell culture media. Immunohistochemistry in surgical specimens revealed weak or no cytoplasmic staining for ChAT in normal colon enterocytes (n = 25) whereas half of colon cancer specimens (n = 24) exhibited moderate to strong staining (P < 0.005). We conclude that ACh is an autocrine growth factor in colon cancer. Mechanisms that regulate colon epithelial cell production and release of ACh warrant further investigation.
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