Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation.
Chronic exposure to tobacco smoke, which contains over 60 tumor-initiating carcinogens, is the major risk factor for development of lung cancer, accounting for a large portion of cancer-related deaths worldwide. It is well established that tobacco smoke is a tumor initiator, but we asked whether it also acts as a tumor promoter once malignant initiation, such as caused by K-ras activation, has taken place. Here we demonstrate that repetitive exposure to tobacco smoke promotes tumor development both in carcinogen-treated mice and in transgenic mice undergoing sporadic K-ras activation in lung epithelial cells. Tumor promotion is due to induction of inflammation that results in enhanced pneumocyte proliferation and is abrogated by IKKbeta ablation in myeloid cells or inactivation of JNK1.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, CA 92093-0723, USA.
Hiroyuki
H
Takahashi
Hisanobu
H
Ogata
Reiko
R
Nishigaki
David H
DH
Broide
Michael
M
Karin
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D011905:Genes, ras / Q000235:genetics; D051550:I-kappa B Kinase / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009602:Nitrosamines / Q000633:toxicity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
D002273:Carcinogens; D009602:Nitrosamines; D014028:Tobacco Smoke Pollution; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D051550:I-kappa B Kinase; D048055:Mitogen-Activated Protein Kinase 8