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

Oncogene volume 21, pages 2171–2180 (2002)Cite this article

A Corrigendum to this article was published on 19 November 2002

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Abstract

Activation of peroxisome proliferator-activated receptor (PPAR)-γ 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-γ. 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-γ expression, whereas its induction was clearly observed in differentiated adipocytes expressing PPAR-γ. 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-γ by TZDs could cause growth inhibition and apoptosis of NSCLC cells and that GADD153 might be a candidate factor implicated in these processes.

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Acknowledgements

We are grateful to Drs NJ Holbrook and AJ Fornace Jr (National Institute on Aging, Gerontology Research Center, NIH) for supplying the promoter of the human GADD153 gene, and to Dr RA Weinberg, (Department of Biology, MITT) for supplying a vector for E2F-5. We thank Ms K Takagi, Ms I Odagiri and Ms M Taguchi for technical assistance. This work was supported in part by grants-in-aid from the Ministry of Health, Labour and Welfare of Japan (to M Mori).

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Authors and Affiliations

  1. First Department of Internal Medicine, Gunma University School of Medicine, Maebashi, 371-8511, Japan

    Teturou Satoh, Mitsuo Toyoda, Hideki Hoshino, Tsuyoshi Monden, Masanabu Yamada, Hiroyuki Shimizu & Matsumoto Mori

  2. Institute for Molecular and Cellular Regulation, Gunma University School of Medicine, Maebashi, 371-8511, Japan

    Kaoru Miyamoto

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  1. Teturou Satoh
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Correspondence to Matsumoto Mori.

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Satoh, T., Toyoda, M., Hoshino, H. et al. Activation of peroxisome proliferator-activated receptor-γ stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells. Oncogene 21, 2171–2180 (2002). https://doi.org/10.1038/sj.onc.1205279

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