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Peroxisome proliferator-activated receptor-γ activation inhibits tumor progression in non-small-cell lung cancer

Oncogene volume 23, pages 100–108 (2004)Cite this article

Abstract

The peroxisome proliferator-activated receptor-gamma (PPAR-γ) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors and a crucial regulator of cellular differentiation. Differentiation-inducing and antiproliferative effects of PPAR-γ suggest that PPAR-γ agonists might be useful as effective anticancer agents. Few studies have examined the efficacy of these agonists in animal models of tumorigenesis, and their mechanism(s) of action are still not clear. Our studies indicate higher PPAR-γ expression in primary tumors from non-small-cell lung cancer (NSCLC) patients when compared to normal surrounding tissue. The expression of PPAR-γ was also observed in several NSCLC lines. The treatment of lung adenocarcinoma cells (A549) with troglitazone (Tro), a PPAR-γ ligand, enhanced PPAR-γ transcriptional activity and induced a dose-dependent inhibition of A549 cell growth. The observed growth arrest was predominantly due to the inhibition of cell proliferation without significant induction of apoptosis. Cell cycle analysis of Tro-treated cells revealed a cell cycle arrest at G0/G1 with concomitant downregulation of G0/G1 cyclins D and E. In addition, Tro treatment stimulated sustained Erk1/2 activation in A549 cells, suggesting the activation of a differentiation-inducing pathway. Furthermore, treatment of A549 tumor-bearing SCID mice with Tro or Pio inhibited primary tumor growth by 66.7% and significantly inhibited the number of spontaneous lung metastatic lesions. Collectively, our data demonstrate that activation of PPAR-γ impedes lung tumor progression and suggest that PPAR-γ ligands may serve as potential therapeutic agents for NSCLC.

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Acknowledgements

We thank Dr Todd Leff (Wayne State University, Detroit, MI, USA) for providing PPRE-tk-Luc and tk-Luc plasmids, Sarah Alousie (Wayne State University, Detroit, MI, USA) for technical help with Immunohistochemistry, and members of the Flow cytometry core facility (University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA) for flow cytometric analysis. VG Keshamouni is a Parker B Francis Fellow in Pulmonary Research. This research is supported by funds from NIH Grants P050 HL60289, HL57243 (TJS), and K08 HL070068 (RCR) and American Lung Association Grant RG-134-N (VGK).

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Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, 48109, MI, USA

    Venkateshwar G Keshamouni, Raju C Reddy, Douglas A Arenberg, Binju Joel, Victor J Thannickal & Theodore J Standiford

  2. Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, 48109, MI, USA

    Gregory P Kalemkerian

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  1. Venkateshwar G Keshamouni
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Correspondence to Theodore J Standiford.

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Keshamouni, V., Reddy, R., Arenberg, D. et al. Peroxisome proliferator-activated receptor-γ activation inhibits tumor progression in non-small-cell lung cancer. Oncogene 23, 100–108 (2004). https://doi.org/10.1038/sj.onc.1206885

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