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Tumor suppression by apoptotic and anti-angiogenic effects of mortalin-targeting adeno-oncolytic virus

 Ji Young Yoo  ;  Jihoon Ryu  ;  Ran Gao  ;  Tomoko Yaguchi  ;  Sunil C. Kaul  ;  Renu Wadhwa  ;  Chae-Ok Yun 
 JOURNAL OF GENE MEDICINE, Vol.12(7) : 586-595, 2010 
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Adenoviridae/metabolism ; Angiogenesis Inhibitors/metabolism* ; Animals ; Apoptosis* ; Cell Line, Tumor ; Cytoprotection ; HSP70 Heat-Shock Proteins/metabolism* ; Humans ; Mice ; Neoplasms/blood supply* ; Neoplasms/pathology ; Neoplasms/therapy* ; Oncolytic Virotherapy/methods* ; Oncolytic Viruses/metabolism* ; RNA, Small Interfering/metabolism ; Transfection ; Tumor Suppressor Protein p53/metabolism ; Xenograft Model Antitumor Assays
adeno-oncolytic viruses ; angiogenesis ; apoptosis ; cancer therapy ; mortalin ; siRNA
BACKGROUND: Adeno-oncolytic (Adon) viruses offer an effective cancer therapeutic tool with several advantages, including wide host cell permeability, high transduction efficiency, safety, tumor selectivity, non-invasiveness, high genetic modifiability and high level of expression of the integrated transgenes. Armed Adon viruses in which the therapeutic efficacy of virus is enhanced by their coupling with cytotoxic, anti-angiogenic or anti-vascular gene products have gained importance because they engage additional mechanisms for tumor cell killing. In the present study, we selected mortalin, a stress chaperone that is tightly involved in human carcinogenesis, constructed a mortalin-targeting Adon (mot-Adon) virus and examined its therapeutic potential both in vitro and in vivo. METHODS: Mortalin-targeting plasmid and viral vectors that harbored mortalin-specific small interfering RNA sequences were constructed. The therapeutic value of these vectors was investigated in vitro and in vivo by cell culture and nude mice tumor models. RESULTS: We demonstrate that the mot-Adon virus has selective cytotoxicity for human cancer cells in vitro. Retrovirus-mediated overexpression of mortalin protected the cells against mot-Adon virus, confirming that mortalin silencing was the real cause of cancer cell death. Although mortalin overexpression enhanced malignant properties of cancer cells in breast xenograft models, mot-Adon virus elicited an enhanced anti-tumor effect. Immunohistochemical examination of the tumors showed that the mot-Adon virus caused enhanced apoptosis (mediated by reactivation of p53) and suppression of microvessel formation. CONCLUSIONS: Mortalin is up-regulated in a large variety of tumors and hence mot-Adon virus is proposed as a candidate cancer therapeutic agent
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5. Research Institutes (연구소) > Institute for Cancer Research (암연구소) > 1. Journal Papers
Yonsei Authors
Yun, Chae Ok(윤채옥)
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