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Survivin silencing and TRAIL expression using oncolytic adenovirus increase anti-tumorigenic activity in gemcitabine-resistant pancreatic cancer cells

 Zhezhu Han  ;  Seungha Lee  ;  Suyeon Je  ;  Chi-Yong Eom  ;  Hye Jin Choi  ;  Jae J. Song  ;  Joo-Hang Kim 
 APOPTOSIS, Vol.21(3) : 351-364, 2016 
Journal Title
Issue Date
Adenoviridae ; Animals ; Antimetabolites, Antineoplastic/therapeutic use* ; Apoptosis ; Cell Line, Tumor ; Combined Modality Therapy ; Deoxycytidine/analogs & derivatives* ; Deoxycytidine/therapeutic use ; Down-Regulation ; Drug Resistance, Neoplasm/genetics* ; Female ; HEK293 Cells ; Humans ; Inhibitor of Apoptosis Proteins/genetics* ; Mice ; Mice, Nude ; Oncolytic Virotherapy/methods* ; Oncolytic Viruses* ; Pancreatic Neoplasms/therapy* ; RNA Interference ; RNA, Small Interfering/genetics ; TNF-Related Apoptosis-Inducing Ligand/genetics* ; Xenograft Model Antitumor Assays
Gemcitabine ; Oncolytic adenovirus ; Pancreatic cancer ; Survivin ; TRAIL ; shRNA
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Joo Hang(김주항)
Song, Jae Jin(송재진) ORCID logo https://orcid.org/0000-0001-8183-9550
Choi, Hye Jin(최혜진) ORCID logo https://orcid.org/0000-0001-5917-1400
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