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Melanoma Differentiation Associated Gene-7, mda-7/Interleukin-24, Induces Apoptosis in Prostate Cancer Cells by Promoting Mitochondrial Dysfunction and Inducing Reactive Oxygen Species

¹ Departments of Pathology,
² Urology, and
³ Neurosurgery, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York;
⁴ Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia;
⁵ Department of Medicine, Mount Sinai Medical Center, New York, New York; and
⁶ The Burnham Institute, La Jolla, California

Mda-7/IL-24 (Ad.mda-7) is a novel cytokine gene belonging to the interleukin (IL) 10 gene superfamily. Adenoviral-mediated delivery of mda-7/IL-24 causes growth suppression and apoptosis in a wide spectrum of cancer cells, including prostate, without harming normal cells. We now demonstrate that Ad.mda-7 selectively induces apoptosis in prostate cancer cells by promoting mitochondrial dysfunction and reactive oxygen species (ROS) production. Antioxidants (N-acetyl-L-cysteine and Tiron) and inhibitors of mitochondrial permeability transition (cyclosporine A and bongkrekic acid) inhibit Ad.mda-7-induced mitochondrial dysfunction and apoptosis. Conversely, agents augmenting ROS production (arsenic trioxide, NSC656240, and PK11195) facilitate Ad.mda-7-induced apoptosis. Ectopic expression of Bcl-2 and Bcl-x_L inhibits mitochondrial changes, ROS production, and apoptosis providing additional support for an association between mitochondrial dysfunction and Ad.mda-7 action. These studies present definitive evidence that changes in mitochondrial function and ROS production are key components associated with selective killing of prostate cancer cells by mda-7/IL-24.

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