Tumor suppressor XIAP‐Associated factor 1 (XAF1) cooperates with tumor necrosis factor‐related apoptosis‐inducing ligand to suppress colon cancer growth and trigger tumor regression |
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Authors: | Shui Ping Tu MD PhD Yun Wei Sun MD PhD Jian Tao Cui MS Bing Zou MD PhD Marie C M Lin PhD Qing Gu PhD Shi Hu Jiang MD Hsiang Fu Kung PhD Robert G Korneluk PhD Benjamin C Y Wong MD PhD |
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Institution: | 1. Department of Gastroenterology, Rui‐jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China;2. Department of Medicine, University of Hong Kong, Hong KongFax: (011) 8621‐64333414;3. Department of Medicine, University of Hong Kong, Hong Kong;4. Department of Chemistry, University of Hong Kong, Hong Kong;5. The Center for Emerging Infectious Diseases, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong;6. Molecular Genetics Research Laboratory, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada |
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Abstract: | BACKGROUND: XIAP‐associated factor 1 (XAF1) antagonizes the anticaspase activity of XIAP (X‐linked inhibitor of apoptosis) and functions as a tumor suppressor in colon cancer. The tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is known as a potential anticancer agent. In this study, the synergistic effect of XAF1 and TRAIL on colon cancer growth was investigated. METHODS: Adeno‐XAF1 virus was generated and purified. Cell apoptosis was detected by flow‐cytometry and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling assay. Protein expression of the different genes was determined by Western blot analysis. Tumorigenesis and tumor growth were assessed in subcutaneous nude mouse xenograft experiments. RESULTS: Stable overexpression of XAF1‐sensitized colon cancer cells to TRAIL‐induced apoptosis significantly increased the activity of caspase 3, 7, 8, and 9; released cytochrome c; and down‐regulated XIAP, survivin, and c‐IAP‐2. The restoration of XAF1 expression mediated by adenovirus (adeno‐XAF1) directly induced apoptosis, and synergized TRAIL‐induced apoptosis in colon cancer cells. Ex vivo transduction of adeno‐XAF1 suppressed colon cancer formation in vivo. Furthermore, adeno‐XAF1 treatment of mice significantly inhibited tumor growth, strongly enhanced TRAIL‐induced apoptosis and antitumor activity in colon cancer xenograft models in vivo, and markedly prolonged the survival. Notably, the combined treatment with adeno‐XAF1 and TRAIL completely eradicated the established tumors without detectable toxicity in normal tissue. CONCLUSIONS: The combined restoration of XAF1 expression and TRAIL treatment may be a potent strategy for colon cancer therapy. Cancer 2010. © 2010 American Cancer Society. |
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Keywords: | XIAP‐associated factor 1 (XAF1) tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) colon cancer apoptosis cancer therapy gene therapy |
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