title: mda-7/IL-24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM.
abstract: 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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Praveen
authors.initials: P
authors.lastname: Bhoopathi
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Health Systems, Department of Surgery, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Lee
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Pradhan
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia. Paul.Fisher@vcuhealth.org.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000256:Adenoviridae / Q000302:isolation & purification; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000502:physiology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006657:Histones / Q000502:physiology; D006801:Humans; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology* / Q000821:virology; D000099180:Interleukin-24
chemical_list: D051033:Apoptosis Inducing Factor; D064007:Ataxia Telangiectasia Mutated Proteins; D020169:Caspases; D006657:Histones; D007378:Interleukins; D000099180:Interleukin-24; C494829:AIFM1 protein, human; C468783:H2AX protein, human; C576324:ATM protein, human