title: Cigarette smoke extract stimulates epithelial-mesenchymal transition through Src activation.
abstract: Epithelial-mesenchymal 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.
authors.affiliation: Andrus Gerontology Center, Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Hongqiao
authors.initials: H
authors.lastname: Zhang
authors.forename: Honglei
authors.initials: H
authors.lastname: Liu
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
authors.forename: Kelvin J A
authors.initials: KJ
authors.lastname: Davies
authors.forename: Fulvio
authors.initials: F
authors.lastname: Ursini
authors.forename: Henry Jay
authors.initials: HJ
authors.lastname: Forman
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000171:Acrolein / Q000008:administration & dosage; D002374:Catalase / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D012906:Smoke / Q000032:analysis*; D014026:Nicotiana; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D012906:Smoke; D000171:Acrolein; D002374:Catalase; D019061:src-Family Kinases; D000111:Acetylcysteine