title: Inhibition of tyrosine kinase activity decreases expression of surfactant protein A in a human lung adenocarcinoma cell line independent of epidermal growth factor receptor.
abstract: Epidermal growth factor (EGF) enhances fetal lung development in vivo and in vitro. Ligand binding to the EGF receptor stimulates an intrinsic receptor tyrosine kinase initiating a signal transduction cascade. We hypothesized that blocking EGF receptor function with tyrosine kinase inhibitors would decrease the expression of surfactant protein A in human pulmonary epithelial cells. Human pulmonary adenocarcinoma cells (NCI-H441) were exposed to genistein (a broad range inhibitor of tyrosine kinases) and tyrphostin AG1478 (a specific inhibitor of EGF receptor tyrosine kinase). Genistein significantly decreased surfactant protein A (SP-A) and SP-A mRNA levels in H441 cells without affecting cell viability. The inhibitory effect of genistein on SP-A content was reversible. In contrast, tyrphostin AG1478 had no effect on SP-A levels despite a greater inhibitory effect than genistein on EGF receptor tyrosine autophosphorylation. Furthermore, treatment of H441 cells with exogenous EGF did not increase SP-A content or mRNA levels beyond baseline. We conclude that inhibition of tyrosine kinase activity other than the EGF receptor decreases the expression of surfactant protein A at a pretranslational level in human pulmonary adenocarcinoma cells. These results suggest the importance of tyrosine kinases in modulating human SP-A synthesis.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City 52242-1083, USA. jonathan-klein@uiowa.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Klein
authors.forename: T A
authors.initials: TA
authors.lastname: McCarthy
mesh_terms: D001597:Benzylidene Compounds / Q000494:pharmacology; D001667:Binding, Competitive; D015152:Blotting, Northern; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D008175:Lung Neoplasms; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011510:Proteolipids / Q000235:genetics / Q000378:metabolism*; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D020032:Tyrphostins
chemical_list: D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D007529:Isoflavones; D009570:Nitriles; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D011799:Quinazolines; D012333:RNA, Messenger; D020032:Tyrphostins; C101044:RTKI cpd; D004815:Epidermal Growth Factor; D019833:Genistein; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases