Muscarinic receptor M3 mediates cell proliferation induced by acetylcholine and contributes to apoptosis in gastric cancer
The muscarinic receptor M3 is an acetylcholine receptor that regulates the activity of numerous fundamental central and peripheral nervous system functions. Recent studies have identified the activation of the M3 receptor in several cancers; however, the role of M3 in human gastric cancer (GC) remains largely unknown. In this study, we demonstrated that the M3 receptor was overexpressed in human GC tissues and was correlated with the cancer stage and with lymph node metastasis. In vitro, the M3 receptor enhanced the proliferation induced by acetylcholine in human GC cells, whereas the knockdown of M3 by a small hairpin RNA (shRNA) inhibited cell proliferation. Furthermore, M3 knockdown caused G2/M phase cell cycle arrest and induced apoptosis in human GC cells. In vivo, M3 knockdown suppressed tumorigenesis and promoted apoptosis in GC xenografts. In addition, we also detected the secretion of acetylcholine (ACh) by human GC cells and observed the co-expression of the M3 receptor and choline acetyltransferase (ChAT), the enzyme necessary for acetylcholine synthesis, in human GC tissues and cells. Taken together, our findings support an oncogenic role for the M3 receptor in gastric cancer, suggesting that M3 antagonists may serve as potential adjuvants to GC therapies. Further study of the underlying molecular mechanism could also lead to the identification of novel therapeutic targets for improved treatment of GC.
KeywordsM3 ACh Proliferation Apoptosis Gastric cancer
This study was funded by the National Natural Science Foundation of China (81272712), the National Natural Science Foundation Project of International Cooperation (NSFC-NIH, 812111519), the Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU, and the Priority Academic Program Development of Jiangsu Higher Education Institutions (KYLX_0936).
Conflicts of interest
- 22.Spindel ER. Muscarinic receptor agonists and antagonists: Effects on cancer. Handb Exp Pharmacol. 2012;451–68.Google Scholar
- 28.Xu R, Shang C, Zhao J, Han Y, Liu J, Chen K, et al. Activation of M3 muscarinic receptor by acetylcholine promotes non-small cell lung cancer cell proliferation and invasion via EGFR/PI3K/AKT pathway. Tumour Biol. 2015.Google Scholar