Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis

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

Research output: Contribution to journalArticle

Abstract

Extracellular proteases have been shown to cooperatively influence matrix degradation and tumor cell invasion through proteolytic cascades, with individual proteases having distinct roles in tumor growth, invasion, migration and angiogenesis. Matrix metalloproteases (MMP)-9 and cathepsin B have been shown to participate in the processes of tumor growth, vascularization and invasion of gliomas. In the present study, we used a cytomegalovirus promoter-driven DNA template approach to induce hairpin RNA (hpRNA)-triggered RNA interference (RNAi) to block MMP-9 and cathepsin B gene expression with a single construct. Transfection of a plasmid vector-expressing double-stranded RNA (dsRNA) for MMP-9 and cathepsin B significantly inhibited MMP-9 and cathepsin B expression and reduced the invasive behavior of SNB19, glioblastoma cell line in Matrigel and spheroid invasion models. Downregulation of MMP-9 and cathepsin B using RNAi in SNB19 cells reduced cell-cell interaction of human microvascular endothelial cells, resulting in the disruption of capillary network formation in both in vitro and in vivo models. Direct intratumoral injections of plasmid DNA expressing hpRNA for MMP-9 and cathepsin B significantly inhibited established glioma tumor growth and invasion in intracranial tumors in vivo. Further intraperitoneal (ip) injections of plasmid DNA expressing hpRNA for MMP-9 and cathepsin B completely regressed pre-established tumors for a long time (4 months) without any indication of these tumor cells. For the first time, these observations demonstrate that the simultaneous RNAi-mediated targeting of MMP-9 and cathepsin B has potential application for the treatment of human gliomas.

Original languageEnglish (US)
Pages (from-to)4681-4689
Number of pages9
JournalOncogene
Volume23
Issue number27
DOIs
StatePublished - Jun 10 2004

Fingerprint

Cathepsin B
Metalloproteases
Glioblastoma
RNA Interference
Gene Expression
Cell Line
Growth
Neoplasms
Glioma
Plasmids
RNA
DNA
Peptide Hydrolases
Double-Stranded RNA
Inhibition (Psychology)
Intraperitoneal Injections
Cytomegalovirus
Cell Communication
Transfection
Down-Regulation

Keywords

  • Angiogenesis
  • Glioma
  • Invasion
  • Proteases
  • siRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis. / Lakka, Sajani S.; Gondi, Christopher S.; Yanamandra, Niranjan; Olivero, William C.; Dinh, Dzung H.; Gujrati, Meena; Rao, Jasti S.

In: Oncogene, Vol. 23, No. 27, 10.06.2004, p. 4681-4689.

Research output: Contribution to journalArticle

Lakka, Sajani S. ; Gondi, Christopher S. ; Yanamandra, Niranjan ; Olivero, William C. ; Dinh, Dzung H. ; Gujrati, Meena ; Rao, Jasti S. / Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis. In: Oncogene. 2004 ; Vol. 23, No. 27. pp. 4681-4689.
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