A survivin-mediated oncolytic adenovirus induces non-apoptotic cell death in lung cancer cells and shows antitumoral potential in vivo.
BACKGROUND
Conditionally replicating adenoviruses or oncolytic adenoviruses, which can replicate selectively in tumor cells and kill them, represent an innovative class of promising cancer therapeutics. Survivin is the smallest member of the inhibitor of apoptosis (IAP) family, which is transcriptionally upregulated exclusively in most malignant tissues but not in normal tissues. It has been reported that activity of the survivin promoter is tumor-specific, which makes the survivin promoter a good candidate to construct oncolytic viral vectors.


METHODS
A luciferase reporter assay was used to determine the activity of the survivin promoter in tumor and normal cells. An oncolytic adenovirus (Ad.SP/E1A) was generated by homologous recombination. The oncolytic efficacy of Ad.SP/E1A was evaluated in cell lines and in a human lung xenograft tumor mouse model.


RESULTS
Survivin expression was highly upregulated in tumor cells both at the protein and mRNA level. The luciferase reporter assay showed that survivin promoter activity is tumor-specific. Ad.SP/E1A expressed E1A selectively in tumor cells and induced cytotoxicity, but not in normal cells. Moreover, in animal experiments, intratumoral administration of Ad.SP/E1A significantly suppressed the growth of xenograft tumors. Further investigation showed that Ad.SP/E1A induced cell death by an apoptosis-independent pathway.


CONCLUSIONS
Ad.SP/E1A could be a potent therapeutic agent for cancer gene therapy. The investigation of the mechanisms of oncolytic virus-induced cell death in this work will shed light on the construction of more powerful vectors for cancer therapy.
Li
Binghua
B
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Liu
Xinran
X
Fan
Junkai
J
Qi
Rong
R
Bo
Linan
L
Gu
Jinfa
J
Qian
Qijun
Q
Qian
Cheng
C
Liu
Xinyuan
X
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D002277:Carcinoma / Q000401:mortality / Q000628:therapy*; D016923:Cell Death; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000138:chemical synthesis; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D000077022:Survivin; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin