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.
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References
Papageorgiou A, Lashinger L, Millikan R, Grossman HB, Benedict W, Dinney CP et al. Role of tumor necrosis factor-related apoptosis-inducing ligand in interferon-induced apoptosis in human bladder cancer cells. Cancer Res 2004; 15: 8973–8979.
Benedict WF, Tao Z, Kim CS, Zhang X, Zhou JH, Adam L et al. IFNα causes marked regression of human bladder cancer growing orthotopically in nude intravesical Ad- mice and overcomes resistance to IFNα protein. Mol Ther 2004; 10: 525–532.
Zhang X-Q, Yang Z, Dong L, Papageorgiou A, McConkey D, Benedict WF . Adenoviral- mediated interferon α overcomes resistance to the interferon protein in various cancer types and has marked bystander effects. Cancer Gene Ther 2007; 14: 241–250.
Zhang X-Q, Dong L, Chapman E, Benedict WF . Conditioned medium from Ad-IFNα infected bladder cancer and normal urothelial cells is cytotoxic to cancer cells but not normal cells: Further evidence for a strong bystander effect. Cancer Gene Ther 2008; 15: 817–822.
Benedict WF, Fisher MB, Cutler DL, Alice A, Young S, Yang Z et al. Results of a Phase 1 trial with intravesical Ad-IFN-α/Syn3 for superficial bladder cancer including putative marker studies (abstract). In: Proceedings of the 100th Annual Meeting of the American Association for Cancer Research, 2009. Abstract#1449.
Fisher MB, Zhang XQ, McConkey DJ, Benedict WF . Measuring soluble forms of extracellular cytokeratin 18 identifies both apoptotic and necrotic mechanisms of cell death produced by adenoviral-mediated interferon alpha: possible use as a surrogate marker. Cancer Gene Ther 2009; 16: 567–572.
Zhang XQ, Dunner K, Benedict WF . Autophagy is induced by adenoviral-mediated interferon α treatment in interferon resistant bladder cancer and normal urothelial cells as a cell death protective mechanism but not by the bystander factors produced. Cancer Gene Ther 2010; 8: 579–584.
Lin JH, Walter P, Yen B . Endoplasmic reticulum stress in disease pathogenesis. Annu Rev Pathol Mech Dis 2008; 3: 399–425.
Gross A, Jockel J, Wei MC, Korsmeyer SJ . Enforced dimerization of BAX results in its translocation, mitochontrial dysfunction and apoptosis. EMBO J 1998; 17: 3878–3885.
Suzuki M, Youle RJ, Tjandra N . Structure of Bax: Co-regulation of dimer formation and intracellular localization. Cell 2000; 103: 645–654.
Acknowledgements
This study was supported by a GU SPORE in Bladder Cancer (P50 CA91846) Project 5 to WFB.
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Zhang, XQ., Yang, Z. & Benedict, W. 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. Cancer Gene Ther 18, 260–264 (2011). https://doi.org/10.1038/cgt.2010.76
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DOI: https://doi.org/10.1038/cgt.2010.76
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