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Adenoviral-mediated mda-7 expression suppresses DNA repair capacity and radiosensitizes non-small-cell lung cancer cells

Oncogene volume 23, pages 7125–7131 (2004)Cite this article

Abstract

The melanoma differentiation-associated gene-7 (mda-7) was identified by virtue of its enhanced expression in human melanoma cells induced into terminal differentiation. Enforced expression of mda-7 in human cancer cell lines of diverse origins results in the suppression of growth and induction of apoptosis. We have shown that adenoviral-mediated mda-7 (Ad-mda7) radiosensitizes non-small-cell lung cancer (NSCLC) cells by enhancing the apoptotic pathway. To identify the mechanism of this radiosensitization, we examined the level of proteins involved in the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair. Western blot analysis indicated that the expression of NHEJ pathway components Ku70, XRCC4, and DNA ligase IV was downregulated in NSCLC cells – A549 with Ad-mda7 treatment. No such change was observed in normal human CCD16 fibroblasts previously shown not to be radiosensitized by Ad-mda7. The biological significance of these changes of expression of proteins critical for repair of radiation-induced DSBs was confirmed via the analysis of DSB rejoining kinetics using pulsed field gel electrophoresis and assessment of host cell reactivation capacity following Ad-mda7 treatment. Based on these results, we hypothesize that Ad-mda7 sensitizes NSCLC cells to ionizing radiation by suppressing the activity of NHEJ, a pathway essential for repair of radiation-induced DSBs.

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Acknowledgements

This study was supported in part by Grants R41 CA88421, P01 CA78778, P01 CA06294, and P30 CA16672 from the National Cancer Institute and a sponsored research agreement with Introgen Therapeutics, Inc. The vectors used in this research were the kind gift of Introgen Therapeutics, Inc.

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Authors and Affiliations

  1. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Takashi Nishikawa, Anupama Munshi, Michael D Story & Raymond E Meyn

  2. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Sheikh Ismail & Craig Stevens

  3. Introgen Therapeutics Inc., Houston, 77030, TX, USA

    Sunil Chada

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  1. Takashi Nishikawa
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  2. Anupama Munshi
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  7. Raymond E Meyn
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Correspondence to Raymond E Meyn.

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Nishikawa, T., Munshi, A., Story, M. et al. Adenoviral-mediated mda-7 expression suppresses DNA repair capacity and radiosensitizes non-small-cell lung cancer cells. Oncogene 23, 7125–7131 (2004). https://doi.org/10.1038/sj.onc.1207917

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