MACC1 mediates acetylcholine-induced invasion and migration by human gastric cancer cells

Ting Yang,Yang Zhao,Min Shi,Jianling Xia,Fei Cui,Rui Zhou,Wanming He,Zhenzhen Wu

doi:10.18632/oncotarget.7634

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.

Highlights

Emerging evidence indicates that nerves play significant roles in the growth and spread of cancers [13]
On www.impactjournals.com/oncotarget the other hand, ACh induced no significant morphological changes in gastric cancer (GC) cells (Supplementary Figure 1). These results indicate that ACh promotes the invasion/migration of GC cells and contributes to epithelial-mesenchymal transition (EMT) progression
It has long been recognized that perineural invasion (PNI), defined as the process in which tumor cells invade the perineural space of nerves, serves an important role in tumor metastasis [20, 21]

Summary

Introduction

Emerging evidence indicates that nerves play significant roles in the growth and spread of cancers [13]. Among the five mAChR subtypes (M1-M5), the M3 receptor (M3R) appears to play a pivotal role in cancer cell proliferation [6,7,8] and invasion [9, 10]. The metastatic effects of ACh in human gastric cancer (GC) remain far from clear. This prompted us to investigate whether ACh acting via M3Rs can stimulate GC cell invasion, migration and/ or epithelial-mesenchymal transition (EMT) and the mechanism involved

Methods

Results

Conclusion