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Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner

Oncogene volume 22, pages 1164–1180 (2003)Cite this article

Abstract

Malignant gliomas are extremely aggressive cancers currently lacking effective treatment modalities. Gene therapy represents a promising approach for this disease. A requisite component for improving gene-based therapies of brain cancer includes tumor suppressor genes that exhibit cancer constrained inhibitory activity. Subtraction hybridization identified melanoma differentiation associated gene-7 (mda-7) as a gene associated with melanoma cell growth, differentiation and progression. Ectopic expression of mda-7 by means of a replication-incompetent adenovirus (Ad), Ad.mda-7, induces growth suppression and apoptosis selectively in diverse human cancers, without producing any apparent harmful effect in normal cells. We presently demonstrate that Ad.mda-7 induces growth inhibition and apoptosis in malignant human gliomas expressing both mutant and wild-type p53, and these effects correlate with an elevation in expression of members of the growth arrest and DNA damage (GADD) gene family. In contrast, infection with a recombinant Ad expressing wild-type p53, Ad.wtp53, specifically affects mutant p53 expressing gliomas. When tested in early passage normal and immortal human fetal astrocytes, growth inhibition resulting from infection with Ad.mda-7 or Ad.wtp53 is significantly less than in malignant gliomas and no toxicity is evident in these normal cells. Moreover, infection of gliomas with Ad.mda-7 or treatment with purified GST–MDA-7 protein sensitizes both wild-type and mutant p53 expressing tumor cells to the growth inhibitory and antisurvival effects of ionizing radiation, and this response correlates with increased expression of specific members of the GADD gene family. Since heterogeneity in p53 expression is common in evolving gliomas, the present findings suggest that Ad.mda-7 may, in many instances, prove more beneficial for the gene-based therapy of malignant gliomas than administration of wild-type p53.

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Acknowledgements

The present research was supported in part by National Institutes of Health, National Cancer Institute Grants CA35675, CA88906, CA97318 and DK52825, National Institutes of Health, Neurology Stroke Grant NS31492, Department of Defense Grants BC98-0148 and DAMD17-98-1-8053, the Samuel Waxman Cancer Research Foundation and the Chernow Endowment. PBF is the Michael and Stella Chernow Urological Cancer Research Scientist.

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  1. Zao-Zhong Su and Irina V Lebedeva: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Zao-Zhong Su, Irina V Lebedeva, Devanand Sarkar, Rahul V Gopalkrishnan, Moira Sauane & Paul B Fisher

  2. Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, 23298, VA, USA

    Carter Sigmon, Adly Yacoub, Kristoffer Valerie & Paul Dent

  3. Department of Urology, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Paul B Fisher

  4. Department of Neurosurgery, Columbia University, College of Physicians and Surgeons, New York, 10032, NY, USA

    Paul B Fisher

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Su, ZZ., Lebedeva, I., Sarkar, D. et al. Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner. Oncogene 22, 1164–1180 (2003). https://doi.org/10.1038/sj.onc.1206062

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