Smoking attenuates transforming growth factor-β-mediated tumor suppression function through downregulation of Smad3 in lung cancer.
Epidemiologic studies have shown that most cases of lung cancers (85%-90%) are directly attributable to cigarette smoking. Although much information has been gained about the effects of cigarette smoking on various signaling pathways causing lung cancer, nothing is known about the effect of cigarette smoking on the TGF-β-induced tumor suppressor function in lung cancer. To address this issue, lung adenocarcinoma A549 and immortalized bronchial epithelial HPL1A cells were chronically treated with cigarette smoke condensate (CSC) and dimethyl sulfoxide (as a control) to mimic the conditions of long-term cigarette smoking. Prolonged exposure of these cells to CSC resulted in a decrease in Smad3 and Smad4 complex formation and TGF-β-mediated transcription due to reduced expression of Smad3. Long-term CSC treatment reduced apoptosis, increased cell viability, decreased TGF-β-mediated growth inhibition, and enhanced tumorigenicity. The decrease in apoptosis is due to the upregulation of Bcl-2, which is a downstream target of Smad3. Re-expression of Smad3 in the CSC-treated cells restored TGF-β signaling, increased apoptosis, and decreased cell viability and tumorigenicity. Withdrawal of CSC treatment resulted in the restoration of Smad3 expression, reduction in cell viability, and increased TGF-β-mediated growth inhibition. Expression of Smad3 is lower in lung tumors of current smokers than that observed in never-smokers. Collectively, these data provide evidence that cigarette smoking promotes tumorigenicity partly by abrogating TGF-β-mediated growth inhibition and apoptosis by reducing expression of Smad3.
Department of Surgery, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, TN 37232, USA.
Debangshu
D
Samanta
Adriana L
AL
Gonzalez
Nagaraj
N
Nagathihalli
Fei
F
Ye
David P
DP
Carbone
Pran K
PK
Datta
D000107:Acetylation; D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D012907:Smoking / Q000009:adverse effects*; D015996:Survival Rate; D046888:Tissue Array Analysis; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
D006657:Histones; D012333:RNA, Messenger; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta