Inactivation of M2 AChR/NF-κB signaling axis reverses epithelial-mesenchymal transition (EMT) and suppresses migration and invasion in non-small cell lung cancer (NSCLC).

// Qingnan Zhao 1, * , Jinnan Yue 1, * , Chun Zhang 1, * , Xiajing Gu 1 , Hongzhuan Chen 1 , Lu Xu 1 1 Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, China * These authors have contributed equally to this work Correspondence to: Hongzhuan Chen, e-mail: hongzhuan_chen@hotmail.com Lu Xu, e-mail: luxuluxu@yahoo.com Keywords: non-neuronal cholinergic system, NSCLC, EMT, NF-κB, M2 muscarinic receptor Received: May 24, 2015      Accepted: August 10, 2015      Published: August 20, 2015 ABSTRACT Non-neuronal cholinergic system is involved in lung physiology and lung cancer. However, the biochemical events downstream acetylcholine (ACh) receptor activation leading to carcinogenesis and tumor progression are not fully understood. Our previous work has shown that non-neuronal ACh acts as an autoparacrine growth factor to stimulate cell proliferation and promote epithelial-mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) via activation of M2 muscarinic receptor (M2R). The aim of the present study was to delineate the underlying mechanisms linking M2R and lung tumor progression, which may provide potential therapeutic targets to delay lung cancer progression. Inhibition of M2R by antagonist or siRNA suppresses NSCLC cell migratory and invasive capacities, reverses EMT and simultaneously inactivates PI3K/Akt, MAPK ERK and NF-κB p65. On the other hand, M2R activation stimulates NSCLC migration and invasion and promotes EMT via NF-κB p65 activation. Moreover, NF-κB p65 activation induced by M2R activation was partially inhibited by either Akt or ERK inhibitor. Taken together, these results demonstrated for the first time that NF-κB p65 activation is essential in NSCLC progression associated with non-neuronal cholinergic system. Our data suggest that M2R/ERK/Akt/NF-κB axis could be a potential target for NSCLC treatment.