title: Acetylcholine acts through M3 muscarinic receptor to activate the EGFR signaling and promotes gastric cancer cell proliferation.
abstract: Acetylcholine (ACh), known as a neurotransmitter, regulates the functions of numerous fundamental central and peripheral nervous system. Recently, emerging evidences indicate that ACh also plays an important role in tumorigenesis. However, little is known about the role of ACh in gastric cancer. Here, we reported that ACh could be auto-synthesized and released from MKN45 and BGC823 gastric cancer cells. Exogenous ACh promoted cell proliferation in a does-dependent manner. The M3R antagonist 4-DAMP, but not M1R antagonist trihexyphenidyl and M2/4 R antagonist AFDX-116, could reverse the ACh-induced cell proliferation. Moreover, ACh, via M3R, activated the EGFR signaling to induce the phosphorylation of ERK1/2 and AKT, and blocking EGFR pathway by specific inhibitor AG1478 suppressed the ACh induced cell proliferation. Furthermore, the M3R antagonist 4-DAMP and darifenacin could markedly inhibit gastric tumor formation in vivo. 4-DAMP could also significantly enhance the cytotoxic activity of 5-Fu against the MKN45 and BGC823 cells, and induce the expression of apoptosis-related proteins such as Bax and Caspase-3. Together, these findings indicated that the autocrine ACh could act through M3R and the EGFR signaling to promote gastric cancer cells proliferation, targeting M3R or EGFR may provide us a potential therapeutic strategy for gastric cancer treatment.
authors.affiliation: Department of Medical Oncology and Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Huangfei
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Medical Oncology and Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Medical Oncology and Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Qiulin
authors.initials: Q
authors.lastname: Tang
authors.affiliation: Department of Medical Oncology and Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Huanji
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Medical Oncology and Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Wei
authors.affiliation: Department of Medical Oncology and Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology and Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Radiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Qiyong
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Department of Medical Oncology and Laboratory of Molecular Targeted Therapy in Oncology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Bi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D043587:Receptor, Muscarinic M3; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048052:Mitogen-Activated Protein Kinase 3; D000109:Acetylcholine