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Melanoma Differentiation Associated Gene-7/Interleukin-24 Promotes Tumor Cell-Specific Apoptosis through Both Secretory and Nonsecretory Pathways

¹ Departments of Pathology, ² Urology, and ³ Neurosurgery, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, and ⁴ Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia

Melanoma differentiation associated gene-7/interleukin-24 (Mda-7/IL-24), a novel member of the IL-10 family of cytokines, uniquely displays cancer-specific apoptosis-inducing activity. Positive results in ongoing phase I/II clinical trials have strengthened the possibility of its utilization as a cancer gene therapeutic. Previous studies document that signaling events leading to Ad.mda-7-induced transformed cell apoptosis are tyrosine kinase-independent. These results suggest that mda-7/IL-24 cancer cell-specific activity could occur through mechanisms independent of binding to its currently recognized cognate receptors and might even occur independent of receptor function. An adenovirus vector expressing a nonsecreted version of MDA-7/IL-24 protein was generated via deletion of its signal peptide. This nonsecreted protein was as effective as wild-type secreted MDA-7/IL-24 in inducing apoptosis in prostate carcinoma cell lines and displayed transformed cell specificity and localization of MDA-7/IL-24 in the Golgi/endoplasmic reticulum compartments. Our results indicate that mda-7/IL-24-mediated apoptosis can be triggered through a combination of intracellular as well as secretory mechanisms and can occur efficiently in the absence of protein secretion.

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