title: Direct cytotoxicity produced by adenoviral-mediated interferon α gene transfer in interferon-resistant cancer cells involves ER stress and caspase 4 activation.
abstract: Over the past several years we have obtained considerable evidence indicating that adenoviruses-expressing interferon α (Ad-IFNα) can overcome resistance to the IFNα protein itself. Since cancer cells infected with Ad-IFNα also show high perinuclear cytoplasmic IFNα expression, we were interested in whether endoplasmic reticulum (ER) stress and cleavage of caspase 4 could have a major role in Ad-IFNα-produced cancer cell death. Indeed, procaspase 4 was upregulated and cleaved as early as 12 h after Ad-IFNα infection of the cancer cells, which co-localized with IFNα staining and ER tracker. In contrast, immortalized normal human urothelial cells, although exhibiting similar perinuclear IFNα staining, showed no cleaved caspase 4. Caspase 4 cleavage was not blocked by the caspase 8 specific inhibitor zIETD, indicating that caspase 4 activation was independent of caspase 8 activation. Blocking caspase 4 also inhibited activation of caspase 3 in Ad-IFNα containing cells. Finally, the cleaved form of caspase 4 (p10) was detected in Ad-IFNα-positive cancer cells from the urine of a patient following intravesical Ad-IFNα/Syn3 treatment. Therefore, ER stress and activation of caspase 4 appears to be an important mechanism involved in the direct cancer cell death produced by Ad-IFNα and also occurs in the clinical setting.
authors.affiliation: Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: X-Q
authors.initials: XQ
authors.lastname: Zhang
authors.forename: C N P
authors.initials: CN
authors.lastname: Dinney
authors.forename: W F
authors.initials: WF
authors.lastname: Benedict
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D053471:Caspases, Initiator / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D005822:Genetic Vectors / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007120:Immunochemistry; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D018613:Microscopy, Confocal; D034622:RNA Interference
chemical_list: D061945:Caspase Inhibitors; D016898:Interferon-alpha; C093516:CASP4 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053471:Caspases, Initiator