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)

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.

miR‑145‑5p inhibits epithelial‑mesenchymal transition via the JNK signaling pathway by targeting MAP3K1 in non‑small cell lung cancer cells

“…MARVELD1 suppresses EMT in NSCLC cells (28). Inactivation of M2 acetylcholine receptor/nuclear factor-κB signaling axis reverses EMT and suppresses migration and invasion in NSCLC cells (29).…”

Over-regulation of microRNA-133b inhibits cell proliferation of cisplatin-induced non-small cell lung cancer cells through PI3K/Akt and JAK2/STAT3 signaling pathway by targeting EGFR

“…Later, PIP2 is transformed into PIP3, which induces the translocation of AKT into the cytoplasm. P-AKT is an important phosphorylase in vivo that is known as phosphokinase B (PKB) (24). There are many downstream active substrates (24).…”

“…P-AKT is an important phosphorylase in vivo that is known as phosphokinase B (PKB) (24). There are many downstream active substrates (24). Phosphorylation can directly or indirectly affect (activate or inhibit) downstream mTOR as well as Bcl-2, thus playing extensive and complex physiological effects.…”

Contrast‑enhanced computerized tomography combined with a targeted nanoparticle contrast agent for screening for early‑phase non‑small cell lung cancer

“…This is due to NSCLC typically being diagnosed at an advanced stage (11,12). In addition, the aggressiveness of NSCLC contributes to tumor recurrence and poor survival rates for patients (13,14). These reports suggest that the early diagnosis of NSCLC would be a best way to improve the survival of patients with NSCLC.…”