Activation of peroxisome proliferator-activated receptor-gamma by troglitazone (TGZ) inhibits human lung cell growth.
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors and a crucial regulator of cellular differentiation. PPAR-gamma ligands have been demonstrated to inhibit growth of several cancer cells. In this study, two human lung cancer cells (NCI-H23 and CRL-2066) and one human lung normal cell (CRL-202) were used for the experiments. The results showed that in consistence with the loss of viability, troglitazone (TGZ) induced apoptosis of CRL-2066 and NCI-H23 cells but not CCL-202 cells. TGZ upregulated PPAR-gamma expression in all the three lung cell lines, especially in the cancer cells. In association of the time-dependent inhibition of the cell proliferation, TGZ downregulated the expression of Bcl-w and Bcl-2 but activated extracellular signal-regulated kinase (ERK)1/2 and p38, suggesting that the growth-inhibitory effect of TGZ is associated with the reduction of Bcl-w and Bcl-2 and the increase of ERK1/2 and p38 activation. SAPK/JNK activation assay showed a decreased activity in all the three cell lines tested after TGZ treatment. It was also demonstrated that TGZ could activate PPAR-gamma transcriptionally. We conclude that TGZ inhibits growth of human lung cancer cells via the induction of apoptosis and the inhibition of cell growth, at least in part, in a PPAR-gamma-relevant manner. The mechanism of TGZ is associated with the activation of ERK and p38, the reduction of SAPK/JNK activity, and the alteration of Bcl-w and Bcl-2.
Li
Mingyue
M
Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China.
Lee
Tak W
TW
Mok
Tony S K
TS
Warner
Timothy D
TD
Yim
Anthony P C
AP
Chen
George G
GG
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002839:Chromans / Q000494:pharmacology*; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000235:genetics*; D000077288:Troglitazone
D002839:Chromans; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077288:Troglitazone