title: Expression of p53 synergistically augments caspases-mediated apoptosis induced by replication-competent adenoviruses in pancreatic carcinoma cells.
abstract: We examined cytotoxicity of replication-competent type 5 adenoviruses (Ad5) in human pancreatic carcinoma cells with a p53-defective genotype. The replication-competent Ad5 of which E1A gene was activated by exogenous transcriptional regulatory sequences, derived from the midkine and survivin genes, achieved cytotoxicity to the pancreatic carcinoma. These cells were susceptible to replication-incompetent Ad5 expressing the wild-type p53 gene. We also produced the replication-competent Ad5 bearing the same exogenous regulatory sequences and the type 35 Ad-derived fiber-knob region, and showed that the cytotoxicity was comparable to that of the replication-competent Ad5 prototype. We then investigated possible combinatory effects of the fiber-modified replication-competent Ad and Ad5 expressing the wild-type p53 gene, both of which did not interfere respective infections. The combination produced synergistic cytotoxic effects with enhanced cleavages of caspase-3 and PARP molecules, and with increased sub-G1 fractions and annexin V-positive populations although the viral production of the replication-competent Ad was rather suppressed by expressed p53. Pancreatic cells infected with both Ad showed increase of p53 and decrease of MDM2 and p21 levels, compared with those infected with Ad expressing the p53 gene. These data collectively indicated that replication-competent Ad augmented susceptibility of pancreatic cells to apoptosis through upregulated p53 expression.
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.|Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takei
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.|Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.|Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.|Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.|Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Morinaga
authors.affiliation: Division of Respirology, Chiba Cancer Center, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Shingyoji
authors.affiliation: Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Sekine
authors.affiliation: Department of Genetics, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kubo
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tada
authors.affiliation: Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Surgery, School of Medicine, Toho University, Tokyo, Japan.
authors.forename: H
authors.identifier: http://orcid.org/0000-0002-1990-8217
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hiroshima
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan.|Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tagawa
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D017500:Adenovirus E1A Proteins / Q000172:deficiency; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D036022:Capsid Proteins / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D003588:Cytopathogenic Effect, Viral; D003673:Defective Viruses / Q000502:physiology; D016158:Genes, p53; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000502:physiology*; D000078792:Midkine; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D014779:Virus Replication / Q000235:genetics
chemical_list: D017500:Adenovirus E1A Proteins; C107489:BIRC5 protein, human; C493956:CDKN1A protein, human; D036022:Capsid Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; C066254:MDK protein, human; D009414:Nerve Growth Factors; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C018315:hexon capsid protein, Adenovirus; D000078792:Midkine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3