Nicotine Induces Progressive Properties of Lung Adenocarcinoma A549 Cells by Inhibiting Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Expression and Plasma Membrane Localization

Lung cancer remains one of the most common cancer-related deaths worldwide. The cigarette smoking is a risk factor for lung cancer development. Interestingly, the cystic fibrosis transmembrane conductance regulator encoded by CFTR gene, an ATP-binding cassette transporter-class ion channel that conducts chloride and bicarbonate anions across membrane of epithelial cells, has recently been suggested to play a role in the development and progression of many types of cancer. It has been well-documented that mutations of CFTR gene are the cause of cystic fibrosis, the most common fatal hereditary lung disease in Caucasian population; the function of cystic fibrosis transmembrane conductance regulator in the development of lung cancer however has not yet been established. In the present study, we aimed to interrogate the impact of cystic fibrosis transmembrane conductance regulator on the nicotine-promoted progressive potency in lung adenocarcinoma cells by assessing capacities of cystic fibrosis transmembrane conductance regulator to cell migration, invasion, and clonogenicity and the expression of markers of cell proliferation and lung stem cell–related transcription factors in lung adenocarcinoma A549 cells. The exposure of nicotine exhibited an ability to enhance progressive properties of adenocarcinoma cells including A549 cells, HCC827 cells, and PC-9 cells, alone with an inhibition of cystic fibrosis transmembrane conductance regulator protein expression. Remarkably, an overexpression of cystic fibrosis transmembrane conductance regulator significantly inhibited the progressive potency of A549 cells, including capacity of cell migration and invasion and clonogenicity, along with a decreased expression of cell proliferative markers Ki67, p63, and proliferating cell nuclear antigen, and cancer stem cell marker CD133, stem cell pluripotency-related transcription factors octamer-binding transcription factor ¾, and sex-determining region Y-box 2, regardless of the presence of nicotine. In contrast, opposite effects were observed in A549 cells that the cystic fibrosis transmembrane conductance regulator was knockdown by short hairpin RNA to cystic fibrosis transmembrane conductance regulator. This study thus suggests that cystic fibrosis transmembrane conductance regulator may play a tumor suppressor role in lung cancer cells, which may be a novel therapeutic target warranted for further investigation.