Tobacco smoke induces urokinase-type plasminogen activator and cell invasiveness: evidence for an epidermal growth factor receptor dependent mechanism.
Multiple tobacco smoke-related premalignant and malignant lesions develop synchronously or metachronously in various organ sites, including the oral cavity. Both field cancerization and clonal migration seem to contribute to the occurrence of multiple tumors. Although the importance of endogenous factors (e.g., oncogenes) in regulating clonal migration is well established, little is known about the role of exogenous factors. Hence, the main objective of this study was to elucidate the mechanism by which tobacco smoke stimulated the migration of cells through extracellular matrix (ECM). Treatment of MSK-Leuk1 cells with a saline extract of tobacco smoke induced the migration of cells through ECM. Tobacco smoke induced the expression of urokinase-type plasminogen activator (uPA), resulting in plasmin-dependent degradation of ECM and increased cell migration. AG1478, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, a neutralizing antibody to EGFR, or an antibody to amphiregulin, an EGFR ligand, also blocked tobacco smoke-mediated induction of uPA and cell migration through ECM. PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase activity, caused similar inhibitory effects. Taken together, these results suggest that tobacco smoke activated the EGFR-->extracellular signal-regulated kinase 1/2 MAPK pathway, causing induction of uPA. This led, in turn, to increased plasmin-dependent degradation of matrix proteins and enhanced cell migration through ECM. These data strongly suggest that chemicals in tobacco smoke can mimic the effects of oncogenes in regulating uPA-dependent cell invasion through ECM. These findings also strengthen the rationale for determining whether inhibitors of EGFR tyrosine kinase reduce the risk of tobacco smoke-related second primary tumors.
Du
Baoheng
B
Department of Medicine, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York, USA.
Leung
Helen
H
Khan
K M Faisal
KM
Miller
Charles G
CG
Subbaramaiah
Kotha
K
Falcone
Domenick J
DJ
Dannenberg
Andrew J
AJ
D002465:Cell Movement; D004790:Enzyme Induction; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000473:pathology; D007971:Leukoplakia / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D012906:Smoke; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D012906:Smoke; D066246:ErbB Receptors; D014568:Urokinase-Type Plasminogen Activator