title: Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer.
abstract: OBJECTIVE
  The reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer.
  
  
  METHODS
  REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine.
  
  
  RESULTS
  The REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling.
  
  
  CONCLUSIONS
  Ad-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Uchida
authors.forename: Hidenori
authors.initials: H
authors.lastname: Shiraha
authors.forename: Hironari
authors.initials: H
authors.lastname: Kato
authors.forename: Teruya
authors.initials: T
authors.lastname: Nagahara
authors.forename: Masaya
authors.initials: M
authors.lastname: Iwamuro
authors.forename: Junro
authors.initials: J
authors.lastname: Kataoka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Horiguchi
authors.forename: Masami
authors.initials: M
authors.lastname: Watanabe
authors.forename: Akinobu
authors.initials: A
authors.lastname: Takaki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nouso
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Nasu
authors.forename: Takahito
authors.initials: T
authors.lastname: Yagi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kumon
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D018925:Chemokines; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use*; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D000093542:Gemcitabine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: apoptosis; autophagy; dickkopf-related protein; gene therapy; mTOR pathway