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

Ying Jia; Qian Zhang; Zhiyuan Liu; Pan Pan; Yanfei Jia; Ping Zhu; Yang Jiao; Guiyu Kang; Xiaoli Ma

doi:10.1016/j.tox.2022.153120

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

Toxicology. 2022 Mar 15:469:153120. doi: 10.1016/j.tox.2022.153120. Epub 2022 Feb 4.

Authors

Ying Jia¹, Qian Zhang², Zhiyuan Liu³, Pan Pan², Yanfei Jia², Ping Zhu⁴, Yang Jiao², Guiyu Kang⁴, Xiaoli Ma⁵

Affiliations

¹ Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan Shandong, 250013, China; Department of Clinical Laboratory, Taian City Central Hospital, Shandong, 271000, China.
² Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan Shandong, 250013, China.
³ School of Rehabilitation Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250000, China.
⁴ Department of Medical Laboratory, Weifang Medical University, Weifang, 261000, China.
⁵ Research Center of Basic Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan Shandong, 250013, China; Department of Medical Laboratory, Weifang Medical University, Weifang, 261000, China; Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, China. Electronic address: Maxiaoli_jn@sdu.edu.cn.

PMID: 35131329
DOI: 10.1016/j.tox.2022.153120

Abstract

α5-nicotinic acetylcholine receptor (α5-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 α5-nAChR contributes to cigarette smoking-related lung cancer. Here, we identified a functional link between α5-nAChR and NLRP3 inflammasome activation in lung adenocarcinoma (LUAD). The expression of α5-nAChR was correlated with the expression of NLRP3 via STAT3 in LUAD tissues. In vitro, nicotine increased the levels of α5-nAChR, p-STAT3, and NLRP3 inflammasome expression, accompanied by the expression of caspase-1, IL-1β and IL-18. Nicotine-induced activation of p-STAT3 and NLRP3 inflammasome signaling were inhibited by the silencing of α5-nAChR. STAT3 binds to the NLRP3 promoter and α5-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 α5-nAChR and NLRP3 was confirmed in chicken embryo chorioallantoic 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 α5-nAChR/STAT3/NLRP3 axis in lung cancer.

Keywords: Cell migration; Cell proliferation; Lung adenocarcinoma; NLRP3 inflammasome; STAT3; α5-nicotinic acetylcholine receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung* / metabolism
Adenocarcinoma of Lung* / pathology
Adenosine Triphosphate
Animals
Cell Line, Tumor
Cell Proliferation
Chick Embryo
Humans
Inflammasomes / metabolism
Inflammation
Lipopolysaccharides
Lung Neoplasms* / pathology
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Nicotine / toxicity
Receptors, Nicotinic*
Signal Transduction

Substances

Inflammasomes
Lipopolysaccharides
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Receptors, Nicotinic
Nicotine
Adenosine Triphosphate