Synergistic down-regulation of urokinase plasminogen activator receptor and matrix metalloproteinase-9 in SNB19 glioblastoma cells efficiently inhibits glioma cell invasion, angiogenesis, and tumor growth

Sajani S. Lakka, Christopher S. Gondi, Niranjan Yanamandra, Dzung H. Dinh, William C. Olivero, Meena Gujrati, Jasti S. Rao

Research output: Contribution to journalArticle

Abstract

The binding of urokinase plasminogen activator (uPA) to its receptor (uPAR) initiates a proteolytic cascade facilitating the activation of matrix metalloproteinase-9 (MMP-9), which in turn degrades the extracellular matrix. These processes have an established role in tumor invasion and metastasis. Our previous work revealed an inverse association between glioma invasion and the expression of uPAR and MMP-9. In the present study, we used the adenovirus serotype 5 vector system to generate a replication-deficient recombinant adenovirus capable of simultaneously expressing antisense uPAR and antisense MMP-9 (Ad-uPAR-MMP-9). This adenoviral construct is driven by the independent promoter elements cytomegalovirus and bovine growth hormone and SV40 polyadenylation signals to down-regulate key steps in the proteolytic cascade. Ad-uPAR-MMP-9 infection of SNB19 cells significantly decreased uPAR and MMP-9 expression as determined by immunohistochemical and Western blotting analyses. A Matrigel invasion assay revealed marked reduction in the invasiveness of the Ad-uPAR-MMP-9-infected cells compared with parental and vector controls. Tumor spheroids infected with Ad-uPAR-MMP-9 and cocultured with fetal rat brain aggregates did not invade rat brain aggregates, whereas 90-95% of the mock and empty vector-infected cells invaded the rat brain aggregates. Intracranial injection of SNB19 cells infected ex vivo with the Ad-uPAR-MMP-9 antisense bicistronic construct showed decreased invasiveness and tumorigenicity, s.c. injections of the bicistronic antisense construct into established tumors (U87 MG) caused tumor regression. These results support the therapeutic potential of targeting the individual components of the uPAR-MMP-9 by using a single adenovirus construct for the treatment of gliomas and other cancers.

Original languageEnglish (US)
Pages (from-to)2454-2461
Number of pages8
JournalCancer Research
Volume63
Issue number10
StatePublished - May 15 2003

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Urokinase Plasminogen Activator Receptors
Matrix Metalloproteinase 9
Glioblastoma
Glioma
Down-Regulation
Growth
Neoplasms
Adenoviridae
Brain
Polyadenylation
Injections
Plasminogen Activators
Urokinase-Type Plasminogen Activator
Cytomegalovirus
Extracellular Matrix
Western Blotting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Synergistic down-regulation of urokinase plasminogen activator receptor and matrix metalloproteinase-9 in SNB19 glioblastoma cells efficiently inhibits glioma cell invasion, angiogenesis, and tumor growth. / Lakka, Sajani S.; Gondi, Christopher S.; Yanamandra, Niranjan; Dinh, Dzung H.; Olivero, William C.; Gujrati, Meena; Rao, Jasti S.

In: Cancer Research, Vol. 63, No. 10, 15.05.2003, p. 2454-2461.

Research output: Contribution to journalArticle

Lakka, Sajani S. ; Gondi, Christopher S. ; Yanamandra, Niranjan ; Dinh, Dzung H. ; Olivero, William C. ; Gujrati, Meena ; Rao, Jasti S. / Synergistic down-regulation of urokinase plasminogen activator receptor and matrix metalloproteinase-9 in SNB19 glioblastoma cells efficiently inhibits glioma cell invasion, angiogenesis, and tumor growth. In: Cancer Research. 2003 ; Vol. 63, No. 10. pp. 2454-2461.
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abstract = "The binding of urokinase plasminogen activator (uPA) to its receptor (uPAR) initiates a proteolytic cascade facilitating the activation of matrix metalloproteinase-9 (MMP-9), which in turn degrades the extracellular matrix. These processes have an established role in tumor invasion and metastasis. Our previous work revealed an inverse association between glioma invasion and the expression of uPAR and MMP-9. In the present study, we used the adenovirus serotype 5 vector system to generate a replication-deficient recombinant adenovirus capable of simultaneously expressing antisense uPAR and antisense MMP-9 (Ad-uPAR-MMP-9). This adenoviral construct is driven by the independent promoter elements cytomegalovirus and bovine growth hormone and SV40 polyadenylation signals to down-regulate key steps in the proteolytic cascade. Ad-uPAR-MMP-9 infection of SNB19 cells significantly decreased uPAR and MMP-9 expression as determined by immunohistochemical and Western blotting analyses. A Matrigel invasion assay revealed marked reduction in the invasiveness of the Ad-uPAR-MMP-9-infected cells compared with parental and vector controls. Tumor spheroids infected with Ad-uPAR-MMP-9 and cocultured with fetal rat brain aggregates did not invade rat brain aggregates, whereas 90-95{\%} of the mock and empty vector-infected cells invaded the rat brain aggregates. Intracranial injection of SNB19 cells infected ex vivo with the Ad-uPAR-MMP-9 antisense bicistronic construct showed decreased invasiveness and tumorigenicity, s.c. injections of the bicistronic antisense construct into established tumors (U87 MG) caused tumor regression. These results support the therapeutic potential of targeting the individual components of the uPAR-MMP-9 by using a single adenovirus construct for the treatment of gliomas and other cancers.",
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AU - Gondi, Christopher S.

AU - Yanamandra, Niranjan

AU - Dinh, Dzung H.

AU - Olivero, William C.

AU - Gujrati, Meena

AU - Rao, Jasti S.

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