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Peroxisome proliferator-activated receptor-γ (PPARγ) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC)

Oncogene volume 24, pages 1412–1422 (2005)Cite this article

Abstract

Pharmacological activators of peroxisome proliferator-activated receptor-γ (PPARγ) have been shown to inhibit growth of lung tumors largely through growth inhibition and induction of apopotosis. However, since many of these agents engage other effectors, the role of PPARγ in lung tumorigenesis remains poorly defined. To specifically examine PPARγ-mediated events, non-small-cell lung cancer (NSCLC) cells overexpressing PPARγ were established. Overexpression of PPARγ in H2122 adenocarcinoma cells (H2122-PPARγ) blocked anchorage-independent growth compared to cells transfected with empty vector (H2122-LNCX), but had no significant effect on cell proliferation or apoptosis under standard tissue culture conditions. Orthotopic implantation of H2122-PPARγ cells into the lungs of nude rats inhibited tumor growth and metastasis in vivo and prolonged survival compared to implantation of H2122-LNCX cells. Consistent with these findings, H2122-PPARγ cells had an impaired invasiveness as assessed in Transwell assays. In a three-dimensional culture system, H2122-PPARγ cells formed polarized spheroid structures similar to those observed with normal lung epithelial cells. H2122-LNCX cells formed nonpolarized aggregate structures and did not show any of these epithelial properties. These data indicate that inhibitory effects of PPARγ on lung tumorigenesis involve selective inhibition of invasive metastasis, and activation of pathways that promote a more differentiated epithelial phenotype.

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Abbreviations

PPAR:

peroxisome proliferator-activated receptor

NSCLC:

non-small-cell lung cancer

TZD:

thiazolidindione

PPAR-RE:

PPAR response element

NSAIDs:

nonsteroidal anti-inflammatory drugs

P-ERM:

phospho-Ezrin/Radixin/Moesin

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Acknowledgements

This work was supported by grants from the National Institutes of Health (CA103618, CA108610, and CA58187). We thank Drs Lynn Heasley and Peter L Jones for helpful discussion. We also thank Dr Nicholas Barry for his assistance with confocal microscopy.

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Authors and Affiliations

  1. Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, 80262, USA

    Yvette Bren-Mattison, Vicki Van Putten, Daniel Chan, Robert Winn, Mark W Geraci & Raphael A Nemenoff

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  1. Yvette Bren-Mattison
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Correspondence to Raphael A Nemenoff.

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Bren-Mattison, Y., Van Putten, V., Chan, D. et al. Peroxisome proliferator-activated receptor-γ (PPARγ) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC). Oncogene 24, 1412–1422 (2005). https://doi.org/10.1038/sj.onc.1208333

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