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Ionizing radiation enhances therapeutic activity of mda-7/IL-24: overcoming radiation- and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2

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Abstract

Subtraction hybridization applied to terminally differentiating human melanoma cells identified mda-7/IL-24, a cytokine belonging to the IL-10 gene superfamily. Adenoviral-mediated delivery of mda-7/IL-24 (Ad.mda-7) provokes apoptosis selectively in a wide spectrum of cancers in vitro in cell culture, in vivo in human tumor xenograft animal models and in patients with advanced carcinomas and melanomas. In human prostate cancer cells, a role for mitochondrial dysfunction and induction of reactive oxygen species in the apoptotic process has been established. Ectopic overexpression of bcl-xL and bcl-2 prevents these changes including apoptosis induction in prostate tumor cells by Ad.mda-7. We now document that this resistance to apoptosis can be reversed by treating bcl-2 family overexpressing prostate tumor cells with ionizing radiation in combination with Ad.mda-7 or purified GST-MDA-7 protein. Additionally, radiation augments apoptosis induction by mda-7/IL-24 in parental and neomycin-resistant prostate tumor cells. Radiosensitization to mda-7/IL-24 is dependent on JNK signaling, as treatment with the JNK 1/2/3 inhibitor SP600125 abolishes this effect. Considering that elevated expression of bcl-xL and bcl-2 are frequent events in prostate cancer development and progression, the present studies support the use of ionizing radiation in combination with mda-7/IL-24 as a means of augmenting the therapeutic benefit of this gene in prostate cancer, particularly in the context of tumors displaying resistance to radiation therapy owing to bcl-2 family member overexpression.

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Abbreviations

mda-7:

melanoma differentiation associated gene-7

IL-24:

interleukin-24

Ad.mda-7:

adenovirus administered mda-7

PFU:

plaque-forming units

IR:

ionizing radiation

JNK:

c-Jun N-terminal kinase

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Acknowledgements

The present studies were supported in part by: NIH/NCI Grants R01 CA097318, R01 CA098712 and P01 CA104177, the Samuel Waxman Cancer Research Foundation, and the Chernow Endowment (P. B. F.); NIH Grants DK52585, R01 CA88906, R01 CA72955 and P01 CA104177 (P.D.); CaP CURE and GM60554 (J. C. R.). P. B. F. is the Michael and Stella Chernow Urological Cancer Research Scientist and a SWCRF Investigator. P. D. holds the Universal Leaf Professorship in Signaling.

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Author notes

  1. Z-Z Su and I V Lebedeva: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, USA

    Z-Z Su, I V Lebedeva, D Sarkar, L Emdad, P Gupta & P B Fisher

  2. The Burnham Institute, La Jolla, CA, USA

    S Kitada & J C Reed

  3. Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, USA

    P Dent

  4. Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, USA

    P B Fisher

  5. Department of Neurosurgery, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY, USA

    P B Fisher

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  1. Z-Z Su
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  2. I V Lebedeva
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Correspondence to P B Fisher.

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Su, ZZ., Lebedeva, I., Sarkar, D. et al. Ionizing radiation enhances therapeutic activity of mda-7/IL-24: overcoming radiation- and mda-7/IL-24-resistance in prostate cancer cells overexpressing the antiapoptotic proteins bcl-xL or bcl-2. Oncogene 25, 2339–2348 (2006). https://doi.org/10.1038/sj.onc.1209271

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