Cigarette smoke extract stimulates epithelialamesenchymal transition through Src activation

• Published in: Free radical biology & medicine 2012-04, Vol.52 (8), p.1437-1442
• Main Authors: Zhang, Hongqiao, Liu, Honglei, Borok, Zea, Davies, Kelvin JA, Ursini, Fulvio, man, Henry Jay
• Format: Article
• Language: English
• ISSN: 0891-5849
• DOI: 10.1016/j.freeradbiomed.2012.01.024

Epithelialamesenchymal transition (EMT) is implicated in the pathogenesis of lung fibrosis and cancer metastasis, two conditions associated with cigarette smoke (CS). CS has been reported to promote the EMT process. CS is the major cause of lung cancer and nearly half of lung cancer patients are active smokers. Nonetheless, the mechanism whereby CS induces EMT remains largely unknown. In this study we investigated the induction of EMT by CS and explored the underlying mechanisms in the human non-small-cell lung carcinoma (H358) cell line. We demonstrate that exposure to an extract of CS (CSE) decreases E-cadherin and increases N-cadherin and vimentin, markers of EMT, in H358 cells cultured in RPMI 1640 medium with 1% fetal bovine serum. Pretreatment with N-acetylcysteine (NAC), a potent antioxidant and precursor of glutathione, abrogated changes in these EMT markers. In addition, CSE activated Src kinase (shown as increased phosphorylation of Src at Tyr418), and the Src kinase inhibitor PP2 inhibited CS-stimulated EMT changes, suggesting that Src is critical in CSE-stimulated EMT induction. Furthermore, NAC treatment abrogated CSE-stimulated Src activation. However, co-incubation with catalase had no effect on CSE-mediated Src activation. Finally, acrolein, an unsaturated aldehyde present in CSE, caused Src activation. Taken together, these data suggest that CSE initiates EMT through Src, which is activated by CS through redox modification.