Targeting c-Src Reverses Accelerated GPX-1 mRNA Decay in Chronic Obstructive Pulmonary Disease Airway Epithelial Cells

• Published in: American journal of respiratory cell and molecular biology Vol. 62; no. 5; pp. 598 - 607
• Main Authors: Dabo, Abdoulaye J., Ezegbunam, Wendy, Wyman, Anne E., Moon, Jane, Railwah, Christopher, Lora, Alnardo, Majka, Susan M., Geraghty, Patrick, Foronjy, Robert F.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.05.2020
• Subjects: Animals; Antioxidants; Benzodioxoles - pharmacology; Chronic obstructive pulmonary disease; Cigarette smoke; Enzyme Activation - drug effects; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelium; Epithelium - drug effects; Epithelium - pathology; Female; Gene Expression Regulation - drug effects; Glutathione peroxidase; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Humans; Lung - pathology; Lung diseases; Male; Mice; mRNA turnover; Obstructive lung disease; Original Research; Proto-Oncogene Proteins pp60(c-src) - metabolism; Pulmonary Disease, Chronic Obstructive - genetics; Quinazolines - pharmacology; Respiratory tract; Respiratory tract diseases; RNA Stability - genetics; Smoking; Smoking - adverse effects; Src protein; glutathione peroxidase-1; mRNA degradation; cigarette smoke; cellular Src kinase; chronic obstructive pulmonary disease
• ISSN: 1044-1549; 1535-4989; 1535-4989
• DOI: 10.1165/rcmb.2019-0177OC

Enhanced expression of the cellular antioxidant glutathione peroxidase (GPX)-1 prevents cigarette smoke-induced lung inflammation and tissue destruction. Subjects with chronic obstructive pulmonary disease (COPD), however, have decreased airway GPX-1 levels, rendering them more susceptible to disease onset and progression. The mechanisms that downregulate GPX-1 in the airway epithelium in COPD remain unknown. To ascertain these factors, analyses were conducted using human airway epithelial cells isolated from healthy subjects and human subjects with COPD and lung tissue from control and cigarette smoke-exposed A/J mice. Tyrosine phosphorylation modifies GPX-1 expression and cigarette smoke activates the tyrosine kinase c-Src. Therefore, studies were conducted to evaluate the role of c-Src on GPX-1 levels in COPD. These studies identified accelerated mRNA decay in COPD airway epithelial cells. Targeting the tyrosine kinase c-Src with siRNA inhibited mRNA degradation and restored GPX-1 protein levels in human airway epithelial cells. In contrast, silencing the tyrosine kinase c-Abl, or the transcriptional activator Nrf2, had no effect on mRNA stability. The chemical inhibitors for c-Src (saracatinib and dasanitib) restored mRNA levels and GPX-1 activity in COPD airway cells . Similarly, saracatinib prevented the loss of lung Gpx-1 expression in response to chronic smoke exposure . Thus, this study establishes that the decreased GPX-1 expression that occurs in COPD lungs is at least partially due to accelerated mRNA decay. Furthermore, these findings show that targeting c-Src represents a potential therapeutic approach to augment GPX-1 responses and counter smoke-induced lung disease.