Induction of apoptosis in the lung tissue from rats exposed to cigarette smoke involves p38/JNK MAPK pathway.
Smoking is a major cause of human lung cancer. Past studies suggest that apoptosis might influence the malignant phenotype, but little is known about the association between apoptosis and cigarette smoke (CS)-induced lung pathogenesis. Using an in situ cell death detection kit (TA300), the association of CS with apoptosis was determined in a concentration-dependent manner. Furthermore, the expression of related proteins were investigated in the terminal bronchiole areas of the lung tissue from rats exposed to CS. Results showed that the expression of phosphotyrosine proteins was increased significantly in lung tissue of rats exposed to CS from 5 to 15 cigarettes. Using Western blotting and immunoprecipitation assay, Fas, a death receptor, was proved just be one of these phosphotyrosine proteins. CS triggered activation of MAP kinase (p38/JNK or ERK2) pathway, which led to Jun or p53 phosphorylation and FasL induction links Fas phosphorylation. Further, smoke treatment produced an increase in the level of proapoptotic proteins (Bax, t-Bid, cytochrome c and caspase-3), but a decline in Bcl-2, procaspase-8 and procaspase-9 proteins. Thus, CS-induced apoptosis may result from two main mechanisms, one is the activation of p38/JNK-Jun-FasL signaling, and the other is stimulated by the stabilization of p53, increase in the ratio of Bax/Bcl-2, release of cytochrome c; thus, leading to activation of caspase cascade.
Kuo
Wu-Hsien
WH
Institute of Biochemistry and Biotechnology, Chung Shan Medical University, No. 110, Sec. 1, Chien Kuo N. Road, Taichung 402, Taiwan.
Chen
Jing-Hsien
JH
Lin
Hui-Hsuan
HH
Chen
Bi-Chiou
BC
Hsu
Jeng-Dong
JD
Wang
Chau-Jong
CJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D019570:Inhalation Exposure; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D012906:Smoke; D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases