title: MACC1 mediates acetylcholine-induced invasion and migration by human gastric cancer cells.
abstract: The neurotransmitter acetylcholine (ACh) promotes the growth and metastasis of several cancers via its M3 muscarinic receptor (M3R). Metastasis-associated in colon cancer-1 (MACC1) is an oncogene that is overexpressed in gastric cancer (GC) and plays an important role in GC progression, though it is unclear how MACC1 activity is regulated in GC. In this study, we demonstrated that ACh acts via M3Rs to promote GC cell invasion and migration as well as expression of several markers of epithelial-mesenchymal transition (EMT). The M3R antagonist darifenacin inhibited GC cell activity in both the presence and absence of exogenous ACh, suggesting GC cells secrete endogenous ACh, which then acts in an autocrine fashion to promote GC cell migration/invasion. ACh up-regulated MACC1 in GC cells, and MACC1 knockdown using siRNA attenuated the effects of ACh on GC cells. AMP-activated protein kinase (AMPK) served as an intermediate signal between ACh and MACC1. These findings suggest that ACh acts via a M3R/AMPK/MACC1 signaling pathway to promote GC cell invasion/migration, which provides insight into the mechanisms underlying GC growth and metastasis and may shed light on new targets for GC treatment.
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wanming
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Cui
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jianling
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000109:Acetylcholine / Q000378:metabolism* / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology*; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001572:Benzofurans; C544162:MACC1 protein, human; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D034741:RNA, Small Interfering; D043587:Receptor, Muscarinic M3; D015534:Trans-Activators; D014157:Transcription Factors; C101207:darifenacin; D055372:AMP-Activated Protein Kinases; D000109:Acetylcholine
keywords: MACC1; acetylcholine; gastric cancer; invasion; migration