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Direct cytotoxicity produced by adenoviral-mediated interferon α gene transfer in interferon-resistant cancer cells involves ER stress and caspase 4 activation

Cancer Gene Therapy volume 18, pages 609–616 (2011)Cite this article

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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.

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References

  1. Benedict WF, Tao Z, Kim CS, Zhang X, Zhou JH, Adam L et al. Intravesical Ad-IFN alpha causes marked regression of human bladder cancer growing orthotopically in nude mice and overcome resistance to IFN-alpha protein. Mol Ther 2004; 10: 525–532.

    Article  CAS  Google Scholar 

  2. Tao Z, Connor RJ, Ashoori F, Dinney CP, Munsell M, Philopena JA et al. Efficacy of a single intravesical treatment with Ad-IFN/Syn 3 is dependent on dose and urine IFN concentration obtained: implications for clinical investigation. Cancer Gene Ther 2006; 13: 125–130.

    Article  CAS  Google Scholar 

  3. Zhang X-Q, Yang Z, Dong L, Papageorgiou A, McConkey D, Benedict WF . Adenoviral-mediated interferon a overcomes resistance to the interferon protein in various cancer types and has marked bystander effects. Cancer Gene Ther 2007; 14: 241–250.

    Article  CAS  Google Scholar 

  4. Zhang X, Dong L, Chapman E, Benedict WF . Conditioned medium from Ad-IFN-alpha-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; 12: 817–822.

    Article  Google Scholar 

  5. Papageorgiou A, Lashinger L, Millikan R, Benedict WF, Dinney CP, McConkey DJ . Autocrine TRAIL production mediates interferon-induced apoptosis in human bladder cancer cells. Cancer Res 2004; 64: 8973–8979.

    Article  CAS  Google Scholar 

  6. Benedict WF, Fisher MB, Cutler DL, Young AA, Yang Z, O’Donnell MA et al. Results of a Phase 1 trial with intravesical Ad-IFN-a/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.

  7. Fisher MB, Zhang XQ, McConkey DJ, Benedict WF . Measuring soluble forms of extracellular cytokeratin18 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.

    Article  CAS  Google Scholar 

  8. Watanabe T, Shinohara N, Sazawa A, Harabayashi T, Ogiso Y, Koyanagi T et al. An improved intravesical model using human bladder cancer cell lines to optimize gene and other therapies. Cancer Gene Ther 2000; 7: 1575–1580.

    Article  CAS  Google Scholar 

  9. Chapman EJ, Hurst CD, Pitt E, Chambers P, Aveyard JS, Knowles MA . Expression of hTERT immortalizes normal human urothelial cells without inactivation of the p16/Rb pathway. Oncogene 2006; 25: 5037–5045.

    Article  CAS  Google Scholar 

  10. Zhang XQ, Yang Z, Benedict WF . 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 2011; 18: 260–264.

    Article  CAS  Google Scholar 

  11. 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.

    Article  Google Scholar 

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Acknowledgements

This study was supported by Bladder SPORE Grant P50 CA91846 to all authors and a Bladder SPORE Career Development Award to ZY.

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Authors and Affiliations

  1. Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z Yang, X-Q Zhang & W F Benedict

  2. Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    C N P Dinney

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  1. Z Yang
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  2. X-Q Zhang
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  3. C N P Dinney
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  4. W F Benedict
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Correspondence to W F Benedict.

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Yang, Z., Zhang, XQ., Dinney, C. et al. Direct cytotoxicity produced by adenoviral-mediated interferon α gene transfer in interferon-resistant cancer cells involves ER stress and caspase 4 activation. Cancer Gene Ther 18, 609–616 (2011). https://doi.org/10.1038/cgt.2011.26

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