Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin.
Cells dividing at the time of carcinogen exposure are at particular risk for neoplasia. Tobacco smoke contains numerous carcinogens, and we find that smoke, in the absence of exogenous growth factors, is capable of stimulating cell proliferation. The smoke-triggered mechanism includes the generation of oxygen radicals, which in turn stimulate tumor necrosis factor alpha-converting enzyme (a disintegrin and metalloproteinase (ADAM) 17) to cleave transmembrane amphiregulin, a ligand for the epidermal growth factor receptor (EGFR). The binding of amphiregulin to EGFR then stimulates proliferation of lung epithelial cells. These results shed light on the pathogenesis of lung cancer, suggest novel drug targets for the reduction of cancer risk in smokers, and provide insight into how EGFR integrates responses to diverse noxious stimuli.
Lemjabbar
Hassan
H
Biomedical Sciences Program, Cardiovascular Research Institute and Department of Anatomy, University of California, San Francisco, California 94143, USA.
Li
Daizong
D
Gallup
Marianne
M
Sidhu
Sukhvinder
S
Drori
Ehud
E
Basbaum
Carol
C
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D066258:Amphiregulin; D000818:Animals; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D066255:EGF Family of Proteins; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D008168:Lung / Q000166:cytology* / Q000187:drug effects*; D008175:Lung Neoplasms / Q000473:pathology; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D017382:Reactive Oxygen Species; D012907:Smoking; D014407:Tumor Cells, Cultured
C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D002273:Carcinogens; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D016376:Oligonucleotides, Antisense; D017382:Reactive Oxygen Species; D066246:ErbB Receptors; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D010100:Oxygen