Direct gene transfer of adenoviral-mediated interferon α into human bladder cancer cells but not the bystander factors produced induces endoplasmic reticulum stress-related cytotoxicity.

Abstract

We have previously shown that adenoviral-mediated interferon α (Ad-IFNα) is cytotoxic both to cells that are sensitive to recombinant interferon α (IFNα) and to cells which are resistant to IFNα. The cancer cell-specific cytotoxic effects of Ad-IFNα involve three different mechanisms: 1. The direct effect of IFNα production causing cancer cell death in IFNα sensitive cells (1); 2. The direct effect of Ad-IFNα infection and high levels of IFNα expression in IFNα resistant cancer cells (2); and 3. The indirect effect of the Ad-IFNα bystander factors produced (2-4). After Ad-IFNα infection, the cells produce a large amount of perinuclear localized IFN protein. This protein over-load could be a major factor in the direct cancer cell death of those cells infected with Ad-IFNα compared with the indirect cytotoxic effects of the bystander factors produced. Here, we investigated whether a component of Ad-IFN-induced cell death involves protein overload-induced endoplasmic reticulum (ER) stress, using an IFNα-resistant human bladder cancer cell line (KU7), and the normal human urothelial cell line, TERT-NHUC, as preclinical models. We found that the two ER stress response pathways examined were activated in KU7 cells. In contrast, following treatment of the normal TERT-NHUC cells with Ad-IFNα, no ER stress signals were observed. In addition, no ER stress related changes were seen, when KU7 cells were exposed to conditioned medium from Ad-IFNα-treated KU7 cells, indicating that bystander produced cytotoxicity did not involve ER stress. After 24 h of Ad-IFNα infection, the KU7 cancer cells produced spliced X-box binding protein 1 and activating transcription factor 6 protein (ATF6), evoking an ER stress response that could contribute to Ad-IFNα induced apoptosis in these cancer cells. In addition, GADD153/CHOP, GADD34 and BAX were also subsequently modified following activation of the ER stress pathways, thereby signaling downstream effectors in a pro-apoptotic manner.

• Authors: X-Q Zhang, Z Yang, W F Benedict
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 18 Issue 4 Pg. 260-4 (Apr 2011) ISSN: 1476-5500 [Electronic] England
• PMID: 21183949 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• ATF6 protein, human
• Activating Transcription Factor 6
• DNA-Binding Proteins
• Interferon-alpha
• Regulatory Factor X Transcription Factors
• Transcription Factors

Topics

• Activating Transcription Factor 6 (genetics, metabolism)
• Adenoviridae (genetics)
• Apoptosis
• Bystander Effect
• DNA-Binding Proteins (genetics, metabolism)
• Endoplasmic Reticulum (metabolism, pathology)
• Gene Transfer Techniques
• Humans
• Interferon-alpha (administration & dosage, genetics)
• Regulatory Factor X Transcription Factors
• Transcription Factors (genetics, metabolism)
• Tumor Cells, Cultured
• Urinary Bladder Neoplasms (pathology, therapy)