Suppression of glioma invasion and growth by adenovirus-mediated delivery of a bicistronic construct containing antisense uPAR and sense p16 gene sequences.
Our previous studies showed that the urokinase-type plasminogen activator receptor (uPAR) and the p16 tumor suppressor gene play a significant role in glioma invasion. We expected that downregulation of uPAR and overexpression of p16 using a bicistronic vector might cause a additive and cooperative effect in the suppression of glioma invasion and growth. The bicistronic construct (Ad-uPAR/p16)-infected glioblastoma cell lines had significantly lower levels of uPAR and higher levels of p16 than controls. Cell cycle analysis showed the bicistronic vector caused G0/G1 arrest of the cell cycle. In vitro glioblastoma cell growth and invasiveness were inhibited in Ad-uPAR/p16-infected cells compared with controls. Ad-uPAR/p16 suppressed the tumor growth of glioblastoma cell lines in an ex vivo intracerebral tumor model and an in vivo subcutaneous tumor model. Our results support the therapeutic potential of simultaneously targeting uPAR and p16 in the treatment of gliomas.
Adachi
Yoshiaki
Y
Department of Neurological Surgery, Okayama University Medical School, 2-5-1 shikata-cho, Okayama, 700-8558, Japan.
Chandrasekar
Nirmala
N
Kin
Yoshiaki
Y
Lakka
Sajani S
SS
Mohanam
Sanjeeva
S
Yanamandra
Niranjan
N
Mohan
Pamarthi M
PM
Fuller
Gregory N
GN
Fang
Bingliang
B
Fueyo
Juan
J
Dinh
Dzung H
DH
Olivero
William C
WC
Tamiya
Takashi
T
Ohmoto
Takashi
T
Kyritsis
Anthanassios P
AP
Rao
Jasti S
JS
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D001932:Brain Neoplasms / Q000473:pathology* / Q000628:therapy; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D015972:Gene Expression Regulation, Neoplastic; D005796:Genes; D019942:Genes, p16; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D005909:Glioblastoma / Q000473:pathology* / Q000628:therapy; D006801:Humans; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D009368:Neoplasm Transplantation; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins / Q000502:physiology; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors