TY - JOUR
T1 - Muscarinic receptor subtype-3 gene ablation and scopolamine butylbromide treatment attenuate small intestinal neoplasia in Apcmin/+ mice
AU - Raufman, Jean Pierre
AU - Shant, Jasleen
AU - Xie, Guofeng
AU - Cheng, Kunrong
AU - Gao, Xue Min
AU - Shiu, Brian
AU - Shah, Nirish
AU - Drachenberg, Cinthia B.
AU - Heath, Jonathon
AU - Wess, Jürgen
AU - Khurana, Sandeep
N1 - Funding Information:
The Office of Research and Development, Medical Research Service, Department of Veterans Affairs; the National Institutes of Health (CA107345, CA120407, DK067872 to J.P.R., DK081479 to S.K., DK080843 to G.X.); Baltimore Research and Education Foundation to S.K.
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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.
AB - 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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U2 - 10.1093/carcin/bgr118
DO - 10.1093/carcin/bgr118
M3 - Article
C2 - 21705482
AN - SCOPUS:80052395865
SN - 0143-3334
VL - 32
SP - 1396
EP - 1402
JO - Carcinogenesis
JF - Carcinogenesis
IS - 9
ER -