Unique aspects of mda-7/IL-24 antitumor bystander activity: Establishing a role for secretion of MDA-7/IL-24 protein by normal cells

Zhaozhong Su, Luni Emdad, Moira Sauane, Irina V. Lebedeva, Devanand Sarkar, Pankaj Gupta, C. David James, Aaron Randolph, Kirstoffer Valerie, Mark R. Walter, Paul Dent, Paul B. Fisher

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124 Scopus citations

Abstract

Melanoma differentiation associated gene-7 (mda-7) was cloned using subtraction hybridization from terminally differentiated human melanoma cells. Based on structural and functional properties, mda-7 is now recognized as interleukin-24 (IL-24), a new member of the expanding IL-10 gene family. Unique properties of mda-7/IL-24 include its ability to selectively induce growth suppression, apoptosis and radiosensitization in diverse human cancer cells, without causing similar effects in normal cells. The utility of mda-7/IL-24, administered by means of a replication-incompetent adenovirus, as a gene therapy for cancer has recently received validation in patients, highlighting an important phenomenon initially observed in pancreatic tumor cells, namely a 'potent bystander apoptosis-inducing effect' in adjacent tumor cells not initially receiving this gene product. We presently investigated the contribution of mda-7/IL-24 secreted by normal cells in mediating this 'bystander effect', and document that normal cells induced to produce mda-7/IL-24 following infection with recombinant adenoviruses expressing this cytokine secrete mda-7/IL-24, which modifies the anchorage-independent growth, invasiveness, survival and sensitivity to radiation of cancer cells that contain functional IL-20/IL-22 receptors, but not in cancer cells that lack a complete set of receptors. Moreover, the combination of secreted mda-7/IL-24 and radiation engenders a 'bystander antitumor effect' not only in inherently mda-7/IL-24 or radiation-sensitive cancer cells, but also in tumor cells overexpressing the antiapoptotic proteins bcl-2 or bcl-xL and displaying resistance to either treatment alone. The present studies provide definitive evidence that secreted mda-7/IL-24 from normal cells can induce direct antitumor and radiation-enhancing effects that are dependent on the presence of canonical receptors for this cytokine on tumor cells. Moreover, we now describe a novel means of enhancing mda-7/IL-24's therapeutic potential by targeting normal cells to produce and release this cancer-specific apoptosis-inducing cytokine, a strategy that could be employed as an innovative way of using this unique gene product for treating metastatic disease.

Original languageEnglish (US)
Pages (from-to)7552-7566
Number of pages15
JournalOncogene
Volume24
Issue number51
DOIs
StatePublished - Nov 17 2005

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Keywords

  • Apoptosis
  • Cancer gene therapy
  • Diffusion bystander assay
  • Normal-cell-secreted mda-7/IL-24
  • Radiation sensitization
  • Tumor cell invasion

Cite this

Su, Z., Emdad, L., Sauane, M., Lebedeva, I. V., Sarkar, D., Gupta, P., James, C. D., Randolph, A., Valerie, K., Walter, M. R., Dent, P., & Fisher, P. B. (2005). Unique aspects of mda-7/IL-24 antitumor bystander activity: Establishing a role for secretion of MDA-7/IL-24 protein by normal cells. Oncogene, 24(51), 7552-7566. https://doi.org/10.1038/sj.onc.1208911