The role of α5-nicotinic acetylcholine receptor/NLRP3 signaling pathway in lung adenocarcinoma cell proliferation and migration

alpha 5-nicotinic acetylcholine receptor (alpha 5-nAChR) is involved in tobacco smoking-induced lung carcinogenesis. Increasing evidence has highlighted the importance of inflammation in lung cancer and a strong relationship between smoking and the NLR family pyrin domain containing protein 3 (NLRP3) inflammasome. However, it is unclear whether an inflammation-related effect of alpha 5-nAChR contributes to cigarette smoking-related lung cancer. Here, we identified a functional link between alpha 5-nAChR and NLRP3 inflammasome activation in lung adenocarcinoma (LUAD). The expression of alpha 5-nAChR was correlated with the expression of NLRP3 via STAT3 in LUAD tissues. In vitro, nicotine increased the levels of alpha 5-nAChR, p-STAT3, and NLRP3 inflammasome expression, accompanied by the expression of caspase-1, IL-1 beta and IL-18. Nicotine-induced activation of p-STAT3 and NLRP3 inflammasome signaling were inhibited by the silencing of alpha 5-nAChR. STAT3 binds to the NLRP3 promoter and alpha 5-nAChR mediates NLRP3 expression via STAT3. Functionally, the combination of nicotine and LPS/ ATP could significantly enhance cell proliferation and migration compared to nicotine or LPS/ATP alone. Furthermore, the functional link between alpha 5-nAChR and NLRP3 was confirmed in chicken embryo chorioal-lantoic membrane (CAM) and mouse xenograft models. Together, these findings reveal a novel nicotine-mediated signaling pathway: nicotine promotes lung cell proliferation and migration via the alpha 5-nAChR/STAT3/NLRP3 axis in lung cancer.

Automated summary

alpha 5-nicotinic acetylcholine receptor (alpha 5-nAChR) is involved in tobacco smoking-induced lung carcinogenesis. This study identifies a functional link between alpha 5-nAChR and NLRP3 inflammasome activation in lung adenocarcinoma (LUAD), suggesting that nicotine promotes lung cancer cell proliferation and migration via the alpha 5-nAChR/STAT3/NLRP3 axis.