title: Activation of peroxisome proliferator-activated receptor-gamma stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells.
abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-gamma by the thiazolidinedione (TZD) class of antidiabetic drugs elicits growth inhibition in a variety of malignant tumors. We clarified the effects of TZDs on growth of human non-small cell lung carcinoma (NSCLC) cells that express endogenous PPAR-gamma. Troglitazone and pioglitazone caused inhibition of cellular growth and induced apoptosis of NSCLC cells in a time- and dose-dependent manner. Subtraction cloning analysis identified that troglitazone stimulated expression of the growth arrest and DNA-damage inducible (GADD)153 gene, and the increased expression of GADD153 mRNA was also confirmed by an array analysis of the 160 apoptosis-related genes. Western blot analysis revealed that troglitazone also increased GADD153 protein levels in a time-dependent manner. Troglitazone did not stimulate GADD153 mRNA levels in undifferentiated 3T3-L1 cells lacking PPAR-gamma expression, whereas its induction was clearly observed in differentiated adipocytes expressing PPAR-gamma. Activity of the GADD153 promoter occurred in a NSCLC cell line in transient transcription assays and was significantly stimulated by troglitazone, although binding of PPAR/retinoid X receptor heterodimer was not detected in the promoter region in gel retardation assays. Inhibition of GADD153 gene expression by an antisense phosphorothionate oligonucleotide attenuated the troglitazone-induced growth inhibition. These findings collectively indicated that activation of PPAR-gamma by TZDs could cause growth inhibition and apoptosis of NSCLC cells and that GADD153 might be a candidate factor implicated in these processes.
authors.affiliation: First Department of Internal Medicine, Gunma University School of Medicine, Maebashi 371-8511, Japan.
authors.forename: Teturou
authors.initials: T
authors.lastname: Satoh
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Toyoda
authors.forename: Hideki
authors.initials: H
authors.lastname: Hoshino
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Monden
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yamada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Kaoru
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mori
authors.forename: Masanabu
authors.initials: M
authors.lastname: Yamada
authors.forename: Matsumoto
authors.initials: M
authors.lastname: Mori
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003001:Cloning, Molecular; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D050700:E2F5 Transcription Factor; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; D050700:E2F5 Transcription Factor; C092558:E2F5 protein, human; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D051742:Transcription Factor CHOP; C089946:2,4-thiazolidinedione