title: Activation of M3 muscarinic receptor by acetylcholine promotes non-small cell lung cancer cell proliferation and invasion via EGFR/PI3K/AKT pathway.
abstract: Acetylcholine (ACh), which can be synthesized and secreted by cancer cells, has been reported to play an important role in tumor progression. ACh acts its role through activation of its receptors, muscarinic receptor (mAChR), and nicotinic receptor (nAChR). As a member of mAChR, M3 muscarinic receptor (M3R) is often highly expressed in many cancers. Activation of M3R by ACh participates in the proliferation, differentiation, transformation, and carcinogenesis of cancer. However, the effect of M3R activation on non-small cell lung cancer (NSCLC) remains unclear. Here, our study found that ACh dose-dependently promoted the proliferation, invasion, and migration of NSCLC cells. After silencing of M3R, the biological functions of ACh in NSCLC cells were greatly attenuated. Furthermore, ACh stimulation increased the production of IL-8 and time-dependently induced the activation of EGFR, PI3K, and AKT through M3R. In addition, ACh stimulated the activation of PI3K and AKT via EGFR activity, and blocking of PI3K/AKT pathway by special inhibitor LY294002 suppressed the ACh-mediated proliferation, invasion, and migration of NSCLC cells. Taken together, these findings indicate that activation of M3R by ACh enhances the proliferation, invasion, and migration of NSCLC cells. ACh-induced activation of EGFR/PI3K/AKT pathway and subsequent IL-8 upregulation may be one of the important mechanisms of M3R function. Thus, M3R could be a potential therapeutic target for the treatment of NSCLC.
authors.affiliation: Department of Thoracic Surgery, Shengjing Hospital, China Medical University, No. 36 San Hao Street, Shenyang, 110004, Liaoning Province, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Xu
authors.forename: Chao
authors.initials: C
authors.lastname: Shang
authors.forename: Jungang
authors.initials: J
authors.lastname: Zhao
authors.forename: Yun
authors.initials: Y
authors.lastname: Han
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Kuanbing
authors.initials: K
authors.lastname: Chen
authors.forename: Wenjun
authors.initials: W
authors.lastname: Shi
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D016209:Interleukin-8; D043587:Receptor, Muscarinic M3; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000109:Acetylcholine