Tumor suppression by apoptotic and anti-angiogenic effects of mortalin-targeting adeno-oncolytic virus.
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.
Yoo
Ji Young
JY
Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Korea.
Ryu
Jihoon
J
Gao
Ran
R
Yaguchi
Tomoko
T
Kaul
Sunil C
SC
Wadhwa
Renu
R
Yun
Chae-Ok
CO
D000256:Adenoviridae / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D019610:Cytoprotection; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D018840:HSP70 Heat-Shock Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C080352:mortalin