Data from <i>mda-7/IL-24</i> Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM

Abstract

<div>Abstract<p>Advanced stages of neuroblastoma, the most common extracranial malignant solid tumor of the central nervous system in infants and children, are refractive to therapy. Ectopic expression of melanoma differentiation-associated gene-7/interleukin-24 (<i>mda-7/IL-24</i>) promotes broad-spectrum antitumor activity <i>in vitro, in vivo</i> in preclinical animal models, and in a phase I clinical trial in patients with advanced cancers without harming normal cells. <i>mda-7/IL-24</i> exerts cancer-specific toxicity (apoptosis or toxic autophagy) by promoting endoplasmic reticulum stress and modulating multiple signal transduction pathways regulating cancer cell growth, invasion, metastasis, survival, and angiogenesis. To enhance cancer-selective expression and targeted anticancer activity of <i>mda-7/IL-24</i>, we created a tropism-modified <i>cancer terminator virus (</i>Ad.5/3-<i>CTV)</i>, which selectively replicates in cancer cells producing robust expression of <i>mda-7/IL-24</i>. We now show that Ad.5/3-<i>CTV</i> induces profound neuroblastoma antiproliferative activity and apoptosis in a caspase-3/9–independent manner, both <i>in vitro</i> and <i>in vivo</i> in a tumor xenograft model. Ad.5/3-<i>CTV</i> promotes these effects through a unique pathway involving apoptosis-inducing factor (AIF) translocation into the nucleus. Inhibiting AIF rescued neuroblastoma cells from Ad.5/3-<i>CTV</i>–induced cell death, whereas pan-caspase inhibition failed to promote survival. Ad.5/3-<i>CTV</i> infection of neuroblastoma cells increased ATM phosphorylation instigating nuclear translocation and increased γ-H2AX, triggering nuclear translocation and intensified expression of AIF. These results were validated further using two ATM small-molecule inhibitors that attenuated PARP cleavage by inhibiting γ-H2AX, which in turn inhibited AIF changes in Ad.5/3-<i>CTV–</i>infected neuroblastoma cells. Taken together, we elucidate a novel pathway for <i>mda-7/IL-24</i>–induced caspase-independent apoptosis in neuroblastoma cells mediated through modulation of AIF, ATM, and γ-H2AX. <i>Cancer Res; 76(12); 3572–82. ©2016 AACR</i>.</p></div>