Activation of peroxisome proliferator-activated receptor-gamma stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells

Oncogene. 2002 Mar 28;21(14):2171-80. doi: 10.1038/sj.onc.1205279.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Blotting, Western
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Cell Division / drug effects
  • Cloning, Molecular
  • DNA Damage* / drug effects
  • Dose-Response Relationship, Drug
  • E2F5 Transcription Factor
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Oligonucleotides, Antisense / genetics
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear / deficiency
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Thiazoles / pharmacology*
  • Thiazolidinediones*
  • Time Factors
  • Transcription Factor CHOP
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured


  • CCAAT-Enhancer-Binding Proteins
  • DDIT3 protein, human
  • E2F5 Transcription Factor
  • E2F5 protein, human
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Transcription Factor CHOP
  • 2,4-thiazolidinedione