title: Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice.
abstract: M3 subtype muscarinic receptors (CHRM3) are over-expressed in colon cancer. In this study, we used Apc(min/+) mice to identify the role of Chrm3 expression in a genetic model of intestinal neoplasia, explored the role of Chrm3 in intestinal mucosal development and determined the translational potential of inhibiting muscarinic receptor activation. We generated Chrm3-deficient Apc(min/+) mice and compared intestinal morphology and tumor number in 12-week-old Apc(min/+)Chrm3(-/-) and Apc(min/+)Chrm3(+/+) control mice. Compared with Apc(min/+)Chrm3(+/+) mice, Apc(min/+)Chrm3(-/-) mice showed a 70 and 81% reduction in tumor number and volume, respectively (P < 0.01). In adenomas, β-catenin nuclear staining was reduced in Apc(min/+)Chrm3(-/-) compared with Apc(min/+)Chrm3(+/+) mice (P < 0.02). Whereas Apc gene mutation increased the number of crypt and Paneth cells and decreased villus goblet cells, these changes were absent in Apc(min/+)Chrm3(-/-) mice. To determine whether pharmacological inhibition of muscarinic receptor activation attenuates intestinal neoplasia, we treated 6-week-old Apc(min/+) mice with scopolamine butylbromide, a non-subtype-selective muscarinic receptor antagonist. After 8 weeks of continuous treatment, scopolamine butylbromide-treated mice showed a 22% reduction in tumor number (P = 0.027) and a 36% reduction in tumor volume (P = 0.004) as compared with control mice. Compared with Chrm3 gene ablation, the muscarinic antagonist was less efficacious, most probably due to shorter duration of treatment and incomplete blockade of muscarinic receptors. Overall, these findings indicate that interplay of Chrm3 and β-catenin signaling is important for intestinal mucosal differentiation and neoplasia and provide a proof-of-concept that pharmacological inhibition of muscarinic receptor activation can attenuate intestinal neoplasia in vivo.
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, VA Maryland Health Care System and University of Maryland School of Medicine, Baltimore, MD 21201, USA. jraufman@medicine.umaryland.edu
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Raufman
authors.forename: Jasleen
authors.initials: J
authors.lastname: Shant
authors.forename: Guofeng
authors.initials: G
authors.lastname: Xie
authors.forename: Kunrong
authors.initials: K
authors.lastname: Cheng
authors.forename: Xue-Min
authors.initials: XM
authors.lastname: Gao
authors.forename: Brian
authors.initials: B
authors.lastname: Shiu
authors.forename: Nirish
authors.initials: N
authors.lastname: Shah
authors.forename: Cinthia B
authors.initials: CB
authors.lastname: Drachenberg
authors.forename: Jonathon
authors.initials: J
authors.lastname: Heath
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
authors.forename: Sandeep
authors.initials: S
authors.lastname: Khurana
mesh_terms: D000818:Animals; D002086:Butylscopolammonium Bromide / Q000494:pharmacology*; D005260:Female; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000473:pathology / Q000517:prevention & control*; D007421:Intestine, Small / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000032:analysis
chemical_list: D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D051176:beta Catenin; D002086:Butylscopolammonium Bromide