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Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro

Gene Therapy volume 7, pages 2051–2057 (2000)Cite this article

Abstract

The melanoma differentiation-associated gene-7 (mda-7), cloned from a human melanoma cell line H0–1, is known to induce tumor cell-selective growth inhibition in breast cancer cells in vitro and loss of tumorigenicity ex vivo. Yet, the mechanisms underlying these effects are still unknown. Therefore, we investigated these mechanisms on the molecular level in human non-small cell lung carcinoma (NSCLC) cells in vitro. Overexpression of mda-7 protein by Ad-mda-7 significantly suppressed proliferation and induced G2/M cell cycle arrest in wild-type p53 (A549, H460), and p53-null (H1299) non-small cell lung cancer cell lines, but not in normal human lung fibroblast (NHLF) cells. p53, Bax, and Bak protein expression was up-regulated in wild-type p53 tumor cell lines, but not in p53-null cells, suggesting that an intact p53 pathway was required for Bax and Bak induction. However, in all three cancer cell lines tested, activation of the caspase cascade and cleavage of poly(ADP-ribose) polymerase (PARP) appeared to be independent of the p53 mutational status. Together, these results suggest that apoptosis may be induced via multiple pathways by Ad-mda-7 in lung cancer cells and that Ad-mda-7 has the potential to become a novel therapeutic for clinical cancer gene therapy.

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Acknowledgements

We thank Peggy James for the preparation of the manuscript. This work was supported in part by a Specialized Program of Research Excellence (SPORE) in Lung Cancer (P50-CA70907) (JA Roth) and by a sponsored research agreement with Introgen Therapeutics, Inc.

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, Section of Thoracic Molecular Oncology, The University of Texas, MD Anderson Cancer Center, TX, USA

    T Saeki, C Branch, JA Roth & R Ramesh

  2. Introgen Therapeutics Inc., Houston, TX, USA

    A Mhashilkar & S Chada

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  1. T Saeki
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  2. A Mhashilkar
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  4. C Branch
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Saeki, T., Mhashilkar, A., Chada, S. et al. Tumor-suppressive effects by adenovirus-mediated mda-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Ther 7, 2051–2057 (2000). https://doi.org/10.1038/sj.gt.3301330

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  • DOI: https://doi.org/10.1038/sj.gt.3301330

Keywords

  • mda-7
  • gene therapy
  • apoptosis
  • lung cancer
  • caspase

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