Cigarette Smoke Induces Gefitinib Resistance in NSCLC Cells
via ROS/Sirt3/SOD2 Pathway.
10.3779/j.issn.1009-3419.2023.106.05
- Author:
Yawan ZI
1
;
Ke LIAO
1
;
Hong CHEN
1
Author Information
1. Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
- Publication Type:Journal Article
- Keywords:
Cigarette smoke;
Gefitinib resistance;
Lung neoplasms;
ROS;
Sirt3/SOD2
- MeSH:
Humans;
Gefitinib/therapeutic use*;
Carcinoma, Non-Small-Cell Lung/metabolism*;
Sirtuin 3/therapeutic use*;
Lung Neoplasms/metabolism*;
Reactive Oxygen Species/therapeutic use*;
Antineoplastic Agents/therapeutic use*;
Cigarette Smoking;
Sincalide/therapeutic use*;
ErbB Receptors/metabolism*;
Drug Resistance, Neoplasm/genetics*;
Cell Line, Tumor
- From:
Chinese Journal of Lung Cancer
2023;26(4):245-256
- CountryChina
- Language:Chinese
-
Abstract:
BACKGROUND:Epidermal growth factor receptor (EGFR) gene mutations are the most common driver mutations in non-small cell lung cancer (NSCLC). To prolong the survival of the patients, EGFR tyrosine kinase inhibitors (TKIs) resistance in NSCLC is a major challenge that needs to be addressed urgently, and this study focuses on investigating the mechanism of cigarette smoke (CS) induced Gefitinib resistance in NSCLC.
METHODS:PC-9 and A549 cells were cultured in vitro and treated with 1 µmol/L Gefitinib for 4 h and 10% cigarette smoke extract (CSE) for 48 h. Western blot was used to detect Sirtuin 3 (Sirt3) and superoxide dismutase 2 (SOD2) protein expressions; DCFH-DA probe was used to detect intracellular reactive oxygen species (ROS); CCK-8 kit was used to detect cell activity, and EdU was used to detect cell proliferation ability. Sirt3 overexpression plasmid (OV-Sirt3) was transfected in PC-9 and A549 cells and treated with 1 µmol/L Gefitinib for 4 h and 10% CSE for 48 h after N-acetylcysteine (NAC) action. The expressions of Sirt3 and SOD2 were detected by Western blot; the ROS level in the cells was detected by DCFH-DA probe, and the cell activity was detected by CCK-8.
RESULTS:CSE induced an increase in the 50% inhibitory concentration (IC50) of both PC-9 and A549 cells to Gefitinib (P<0.01) and enhanced the proliferation of PC-9 and A549 cells, suggesting that CS induced Gefitinib resistance in NSCLC. ROS was involved in CSE-induced Gefitinib resistance (P<0.05). CSE induced low expressions of Sirt3 and SOD2 (P<0.01), and Sirt3/SOD2 was associated with poor prognosis in lung cancer patients (P<0.05). OV-Sirt3 in PC-9 and A549 cells reversed CSE-induced Gefitinib resistance (P<0.05) and significantly reduced ROS production. NAC reversed CSE-induced Gefitinib resistance in PC-9 and A549 cells (P<0.05).
CONCLUSIONS:The ROS/Sirt3/SOD2 pathway is involved in CS-induced Gefitinib resistance in NSCLC.
