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Blocking M2 muscarinic receptor signaling inhibits tumor growth and reverses
epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC)
#MMPMID25778781
Zhao Q
; Gu X
; Zhang C
; Lu Q
; Chen H
; Xu L
Cancer Biol Ther
2015[]; 16
(4
): 634-43
PMID25778781
show ga
Lung cancers express non-neuronal, cholinergic autoparacrine loop, which
facilitates tumor growth. Interruption of M3 muscarinic cholinergic signaling has
been reported to inhibit small cell lung cancer (SCLC) growth. The purpose of
this study is to investigate if blocking autoparacrine muscarinic cholinergic
signaling could inhibit non-small cell lung cancer (NSCLC) growth and possible
underlying mechanisms. Our results showed that PC9 and A549 cells expressed all 5
subtypes of muscarinic receptor (mAChR) and blocking M2 mAChR (M2R) signaling
using selective antagonist methoctramine or short hairpin RNA (shRNA) inhibited
tumor cell proliferation in vitro and in vivo. Consistent with AChR agonists
stimulating p44/42 MAPK (Erk1/2) and Akt phosphorylation, blocking M2R signaling
decreased MAPK and Akt phosphorylation, indicating that non-neuronal ACh
functions as an autoparacrine growth factor signaling in part through activation
of M2R and downstream MAPK and Akt pathways. Importantly, further studies
revealed that blocking M2R signaling also reversed epithelial-mesenchymal
transition (EMT) in vitro and in vivo, indicating that non-neuronal ACh promotes
EMT partially through activation of M2R. These findings demonstrate that M2R
plays a role in the growth and progression of NSCLC and suggest M2R antagonists
may be an efficacious adjuvant therapy for NSCLC.
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