title: Survivin silencing and TRAIL expression using oncolytic adenovirus increase anti-tumorigenic activity in gemcitabine-resistant pancreatic cancer cells.
abstract: 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.
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea. cshan1129@yuhs.ac.|Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, Jilin Province, People's Republic of China. cshan1129@yuhs.ac.|Severance Biomedical Science Institute, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea. cshan1129@yuhs.ac.
authors.forename: Zhezhu
authors.initials: Z
authors.lastname: Han
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea. genius0036@naver.com.
authors.forename: Seungha
authors.initials: S
authors.lastname: Lee
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea. sysy5731@daum.net.
authors.forename: Suyeon
authors.initials: S
authors.lastname: Je
authors.affiliation: STEREO Imaging Group, Seoul Center, Korea Basic Science Institute, Seoul, Republic of Korea. cyeom@kbsi.re.kr.
authors.forename: Chi-Yong
authors.initials: CY
authors.lastname: Eom
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. choihj@yuhs.ac.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea. jjs109@yuhs.ac.|Severance Biomedical Science Institute, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea. jjs109@yuhs.ac.
authors.forename: Jae J
authors.initials: JJ
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. kjhang@yuhs.ac.
authors.forename: Joo-Hang
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000256:Adenoviridae; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D010190:Pancreatic Neoplasms / Q000628:therapy*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Gemcitabine; Oncolytic adenovirus; Pancreatic cancer; Survivin; TRAIL; shRNA