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. 2006 Apr 13;25(16):2339-48. doi: 10.1038/sj.onc.1209271.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Genetic Therapy*
  • Humans
  • Interleukins / genetics*
  • JNK Mitogen-Activated Protein Kinases / physiology
  • MAP Kinase Signaling System
  • Male
  • Phosphorylation
  • Prostatic Neoplasms / chemistry
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy*
  • Proto-Oncogene Proteins c-bcl-2 / analysis*
  • Radiation Tolerance*
  • bcl-X Protein / analysis*


  • Interleukins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • interleukin-24
  • JNK Mitogen-Activated Protein Kinases