Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice

Jean Pierre Raufman, Jasleen Shant, Guofeng Xie, Kunrong Cheng, Xue Min Gao, Brian Shiu, Nirish Shah, Cinthia B. Drachenberg, Jonathon Heath, Jürgen Wess, Sandeep Khurana

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Abstract

M3 subtype muscarinic receptors (CHRM3) are over-expressed in colon cancer. In this study, we used Apcmin/+ 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 inhibitingmuscarinic receptor activation. We generated Chrm3-deficient Apcmin/+ mice and compared intestinal morphology and tumor number in 12-week-old Apcmin/+Chrm3-/- and Apcmin/+Chrm3+/+ controlmice. Compared with Apcmin/+Chrm3+/+ mice, Apcmin/+Chrm3-/- mice showed a 70 and 81% reduction in tumor number and volume, respectively (P < 0.01). In adenomas, b-catenin nuclear staining was reduced in Apcmin/+ Chrm3-/- compared with Apcmin/+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 Apcmin/+Chrm3-/- mice. To determine whether pharmacological inhibition of muscarinic receptor activation attenuates intestinal neoplasia, we treated 6-week-old Apcmin/+ 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 ofmuscarinic 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.

Original languageEnglish (US)
Pages (from-to)1396-1402
Number of pages7
JournalCarcinogenesis
Volume32
Issue number9
DOIs
StatePublished - Sep 9 2011

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Scopolamine Hydrobromide
Muscarinic Receptors
Genes
Neoplasms
Catenins
Muscarinic Antagonists
Tumor Burden
Muscarinic M3 Receptors
Paneth Cells
butyl bromide
Goblet Cells
Genetic Models
Adenoma
Colonic Neoplasms
Pharmacology
Staining and Labeling
Mutation

ASJC Scopus subject areas

  • Cancer Research

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Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice. / Raufman, Jean Pierre; Shant, Jasleen; Xie, Guofeng; Cheng, Kunrong; Gao, Xue Min; Shiu, Brian; Shah, Nirish; Drachenberg, Cinthia B.; Heath, Jonathon; Wess, Jürgen; Khurana, Sandeep.

In: Carcinogenesis, Vol. 32, No. 9, 09.09.2011, p. 1396-1402.

Research output: Contribution to journalArticle

Raufman, JP, Shant, J, Xie, G, Cheng, K, Gao, XM, Shiu, B, Shah, N, Drachenberg, CB, Heath, J, Wess, J & Khurana, S 2011, 'Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice', Carcinogenesis, vol. 32, no. 9, pp. 1396-1402. https://doi.org/10.1093/carcin/bgr118
Raufman, Jean Pierre ; Shant, Jasleen ; Xie, Guofeng ; Cheng, Kunrong ; Gao, Xue Min ; Shiu, Brian ; Shah, Nirish ; Drachenberg, Cinthia B. ; Heath, Jonathon ; Wess, Jürgen ; Khurana, Sandeep. / Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice. In: Carcinogenesis. 2011 ; Vol. 32, No. 9. pp. 1396-1402.
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abstract = "M3 subtype muscarinic receptors (CHRM3) are over-expressed in colon cancer. In this study, we used Apcmin/+ 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 inhibitingmuscarinic receptor activation. We generated Chrm3-deficient Apcmin/+ mice and compared intestinal morphology and tumor number in 12-week-old Apcmin/+Chrm3-/- and Apcmin/+Chrm3+/+ controlmice. Compared with Apcmin/+Chrm3+/+ mice, Apcmin/+Chrm3-/- mice showed a 70 and 81{\%} reduction in tumor number and volume, respectively (P < 0.01). In adenomas, b-catenin nuclear staining was reduced in Apcmin/+ Chrm3-/- compared with Apcmin/+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 Apcmin/+Chrm3-/- mice. To determine whether pharmacological inhibition of muscarinic receptor activation attenuates intestinal neoplasia, we treated 6-week-old Apcmin/+ 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 ofmuscarinic 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.",
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AU - Cheng, Kunrong

AU - Gao, Xue Min

AU - Shiu, Brian

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