Abstract 1502: Adenoviral-mediated interferon α induces endoplasmic reticulum stress related cytotoxicity in human cancer but not normal cells

Abstract

Abstract We have previously shown that adenoviral-mediated interferon α (Ad-IFNα) treatment is specifically cytotoxic to various cancer cells, not only to the cancer cells sensitive to the interferon protein (IFNα), but also to the cells which are resistant to IFNα. We also found that there is very little cytotoxic effect of Ad-IFNα on non-cancer cells. The cancer cell specific toxic effects of Ad-IFNα can be classified into three different mechanisms: 1. Expression and secretion of interferon α protein that results in kill of IFNα sensitive cancer cells; 2. Direct kill of IFNα resistant cancer cells by Ad-IFNα and 3. Cancer cell kill by Ad-IFNα produced bystander factors. After Ad-IFNα infection, the host cells produce a large amount of IFN protein. We hypothesized that this protein over-load is cytotoxic to cancer cells and may be a major reason for Ad-IFNα direct effect. We now report that Ad-IFNα infection induces ER stress and ER stress related apoptosis in human cancer but not normal urothelial cells. In addition we found that the Ad-IFNα produced bystander cytotoxicity was not related to ER stress. To investigate whether Ad-IFNα induced cancer specific cytotoxicity was correlated with the activation of ER stress pathways, the expression of several markers of ER stress was studied. Experiments utilized the interferon resistant human bladder cancer cell line, KU7, and the normal human urothelial cell line, TERT-NHU, for the studies. We found that three ER stress response pathways examined were activated in KU7 cells. In contrast, the ER stress response pathways remained silent in the normal TERT-NHU cells or in KU7 cells treated with conditioned medium from Ad-IFNα treated KU7 cells (to test the effect of bystander factor produced cytotoxicity) the ER stress response pathways remained silent. After 24hr of Ad-IFNα exposure, KU7 cancer cells produced spliced X-box binding protein 1 (sXBP1), activating transcription factor 4 (ATF4) and activating transcription factor (ATF6) protein, and evoked an ER stress response that contribute to Ad-IFNα induced apoptosis in cancer cells. In addition, we found GADD153/CHOP and GADD34 were also upregulated following the activation of the three ER stress pathways, thereby signaling downstream effectors in a pro-apoptotic manner. Ad-IFNα recently has been used in Phase I clinical trial for patient with superficial bladder cancer. The results presented here could provide a mechanistic basis for Ad-IFNα action and support the positive clinical results obtained to date. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1502.