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Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1

Cancer Gene Therapy volume 15, pages 29–39 (2008)Cite this article

Abstract

FUS1 is a novel tumor suppressor gene located in the human chromosome 3p21.3 region. We previously showed that restoration of FUS1 function in 3p21.3-deficient human non-small-cell lung cancer (NSCLC) cells significantly inhibited tumor cell growth in vitro and in vivo. In this study, we evaluated the combined effects of the tumor suppressor FUS1 and the chemotherapeutic drug cisplatin on tumor cell growth and apoptosis induction in NSCLC cells, and explored the molecular mechanism of their mutual action. Exogenous expression of FUS1 by nanoparticle-mediated gene transfer sensitized the response of NSCLC cells to cisplatin, resulting in a 4- to 6-fold increase in tumor-suppressing activity. A systemic treatment with a combination of FUS1-nanoparticles and cisplatin in a human H322 lung cancer orthotopic xenograft mouse model dramatically enhanced the therapeutic efficacy of cisplatin. We also found that the FUS1-enhanced chemosensitivity is associated with the downregulation of MDM2, accumulation of p53 and activation of the Apaf-1-dependent apoptosis pathway. Our results demonstrated an important role of FUS1 in modulating chemosensitivity of lung cancer cells, and suggested that a proper combination of molecular therapeutics such as the proapoptotic tumor suppressor FUS1 and the conventional chemotherapeutic drugs such as cisplatin may be an efficient treatment strategy for human lung cancer.

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Acknowledgements

This work received grant support from the following: NIH/NCI, Specialized Program of Research Excellence Grants CA70970, RO1CA11632 (LJ) and MMHCC U01CA10535201; Department of Defense TARGET Lung Cancer Programs Grant DAMD17-02-1-070; MD Anderson Cancer Center Support Core Grant CA16672 and a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature.

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Authors and Affiliations

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

    W-G Deng, G Wu, K Ueda, K Xu, J A Roth & L Ji

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  1. W-G Deng
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Correspondence to L Ji.

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Deng, WG., Wu, G., Ueda, K. et al. Enhancement of antitumor activity of cisplatin in human lung cancer cells by tumor suppressor FUS1. Cancer Gene Ther 15, 29–39 (2008). https://doi.org/10.1038/sj.cgt.7701094

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