Survivin silencing and TRAIL expression using oncolytic adenovirus increase anti-tumorigenic activity in gemcitabine-resistant pancreatic cancer cells
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  • 作者:Zhezhu Han ; Seungha Lee ; Suyeon Je ; Chi-Yong Eom ; Hye Jin Choi ; Jae J. Song…
  • 关键词:Survivin ; TRAIL ; Gemcitabine ; Pancreatic cancer ; shRNA ; Oncolytic adenovirus
  • 刊名:Apoptosis
  • 出版年:2016
  • 出版时间:March 2016
  • 年:2016
  • 卷:21
  • 期:3
  • 页码:351-364
  • 全文大小:6,938 KB
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  • 作者单位:Zhezhu Han (1) (2) (5)
    Seungha Lee (1)
    Suyeon Je (1)
    Chi-Yong Eom (3)
    Hye Jin Choi (4)
    Jae J. Song (1) (5)
    Joo-Hang Kim (4)

    1. Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea
    2. Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, Jilin Province, People’s Republic of China
    5. Severance Biomedical Science Institute, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea
    3. STEREO Imaging Group, Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea
    4. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
  • 刊物类别:Medicine
  • 刊物主题:Medicine & Public Health
    Oncology
    Cancer Research
    Cell Biology
    Biochemistry
    Virology
  • 出版者:Springer Netherlands
  • ISSN:1573-675X
文摘
In this study, we demonstrated that survivin downregulation with TRAIL expression greatly enhanced the cytotoxic death of pancreatic cancer cells after gemcitabine treatment. Using real-time RT-PCR, we analyzed five survivin shRNAs to identify the best target sequence for suppression of human survivin, with the goal of treating gemcitabine-resistant pancreatic cancer cells. Survivin shRNA 5, corresponding to target 5, showed the greatest reduction in survivin mRNA levels. Furthermore, combined treatment with survivin shRNA-expressing adenovirus with gemcitabine plus TRAIL decreased uncleaved PARP and increased consequent PARP cleavage, which was correlated with the greatest levels of survivin downregulation and cell death. These results indicate that survivin functions as a common mediator of gemcitabine- and TRAIL-induced cell death. Using a nude mouse model implanted with MiaPaCa-2 pancreatic cancer cells, we observed tumor regression induced by an oncolytic adenovirus expressing survivin shRNA and TRAIL plus gemcitabine. Together, our findings provide a strong rationale for treating pancreatic cancer patients with both gemcitabine and oncolytic adenovirus armed with survivin shRNA and TRAIL. Keywords Survivin TRAIL Gemcitabine Pancreatic cancer shRNA Oncolytic adenovirus

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