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 (mda-7/IL-24) promotes broad-spectrum antitumor activity in vitro, in vivo in preclinical animal models, and in a phase I clinical trial in patients with advanced
cancers without harming normal cells. mda-7/IL-24 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 mda-7/IL-24, we created a tropism-modified
cancer terminator virus (
Ad.5/3-CTV), which selectively replicates in
cancer cells producing robust expression of mda-7/IL-24 We now show that
Ad.5/3-CTV induces profound
neuroblastoma antiproliferative activity and apoptosis in a
caspase-3/9-independent manner, both in vitro and in vivo in a
tumor xenograft model.
Ad.5/3-CTV 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-CTV-induced cell death, whereas pan-
caspase inhibition failed to promote survival.
Ad.5/3-CTV
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-CTV-infected
neuroblastoma cells. Taken together, we elucidate a novel pathway for mda-7/IL-24-induced
caspase-independent apoptosis in
neuroblastoma cells mediated through modulation of AIF, ATM, and γ-H2AX.
Cancer Res; 76(12); 3572-82. ©2016 AACR.