Mechanistic aspects of mda-7/IL-24 cancer cell selectivity analysed via a bacterial fusion protein

Moira Sauane, Rahul V. Gopalkrishnan, Heng Tong Choo, Pankaj Gupta, Irina V. Lebedeva, Adly Yacoub, Paul Dent, Paul B. Fisher

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

The human mda-7/IL-24 gene product is normally expressed in melanocytes and certain lymphocyte populations. Loss of expression, a distinctive feature of many tumor suppressor genes, has been documented at RNA and protein levels in association with melanoma progression both in vitro as well as in human tumor-derived material. The MDA-7/IL-24 protein undergoes post-translational processing, including removal of an amino-terminal 48-residue signal peptide and extensive glycosylation prior to its secretion by producing cells. Its inherent cytokine properties have been documented in multiple reports, which have identified and characterized its cognate receptors and activation of the JAK/STAT signaling pathway following ligand/receptor docking. A notable and incompletely understood property of MDA-7/IL-24 is its ability to induce apoptosis in transformed cells, while having marginal growth suppressive effects on normal primary or immortalized cell lines. MDA-7/IL-24 has been delivered to cells, tumor xenografts and patients in clinical trials via a nonreplicating adenovirus (Ad.mda-7). Studies utilizing eukaryotically expressed and purified MDA-7/ IL-24 protein from several sources have recapitulated some of the molecule's reported properties including receptor binding and JAK/STAT activation. Here, we report the properties and characteristics of a bacterially expressed and purified GST-MDA-7 fusion protein. These studies reveal that GST-MDA-7 retains its cancer-selective apoptosis-inducing properties, thereby providing a new reagent that will assist in defining the mechanism of action of this novel cytokine. In addition, retention of tumor-specific activity of GST-MDA-7 suggests that this protein may also have therapeutic applications.

Original languageEnglish (US)
Pages (from-to)7679-7690
Number of pages12
JournalOncogene
Volume23
Issue number46
DOIs
StatePublished - Oct 7 2004

Bibliographical note

Funding Information:
The present research was supported in part by National Institutes of Health Grants CA097318, CA88906, DK52825 and CA098172, DAMD-02-1-0041, the Samuel Waxman Cancer Research Foundation, the Lustgarten Foundation for Pancreatic Cancer Research and the Chernow Endowment. PB Fisher is the Michael and Stella Chernow Urological Cancer Research Scientist. M Sauane is the recipient of a DOD postdoctoral fellowship. We acknowledge Nikollaq Vozhilla for indispensable technical assistance and Sudhindra R Swamy of the optical microscopy facility of the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center for assistance in confocal microscopy.

Keywords

  • Apoptosis
  • Breast cancer
  • Cancer gene therapy
  • GST-MDA-7/IL-24
  • Radiotherapy

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