RNA interference-mediated simultaneous down-regulation of urokinase-type plasminogen activator receptor and cathepsin B induces caspase-8-mediated apoptosis in SNB19 human glioma cells

Christopher S. Gondi, Neelima Kandhukuri, Shakuntala Kondraganti, Meena Gujrati, William C. Olivero, Dzung H. Dinh, Jasti S. Rao

Research output: Contribution to journalArticle

Abstract

The invasive character of gliomas depends on proteolytic cleavage of the surrounding extracellular matrix. Cathepsin B and urokinase-type plasminogen activator receptor (uPAR) together are known to be overexpressed in gliomas and, as such, are attractive targets for gene therapy. In the present study, we used plasmid constructs to induce the RNA interference (RNAi)-mediated down-regulation of uPAR and cathepsin B in SNB19 human glioma cells. We observed that the simultaneous down-regulation of uPAR and cathepsin B induces the up-regulation of proapoptotic genes and initiates a collapse in mitochondrial Δψ. Cathepsin B and uPAR down-regulated cells showed increases in the expression of activated caspase-8 and D FF40/caspase-activated DNase. Nuclear translocation of AIF and Fas ligand translocation to the cell membrane were also observed. Ki67 and X-linked inhibitor of apoptosis protein levels decreased, thereby indicating apoptosis. These results suggest the involvement of uPAR-cathepsin B complex on the cell surface and its role in maintaining the viability of SNB19 glioma cells. In conclusion, RNAi-mediated down-regulation of uPAR and cathepsin B initiates a partial extrinsic apoptotic cascade accompanied by the nuclear translocation of AIF. Our study shows the potential of RNAi-mediated down-regulation of uPAR and cathepsin B in developing new therapeutics for gliomas.

Original languageEnglish (US)
Pages (from-to)3197-3208
Number of pages12
JournalMolecular Cancer Therapeutics
Volume5
Issue number12
DOIs
StatePublished - Dec 1 2006

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Urokinase Plasminogen Activator Receptors
Cathepsin B
Caspase 8
RNA Interference
Glioma
Down-Regulation
Apoptosis
X-Linked Inhibitor of Apoptosis Protein
Fas Ligand Protein
Genetic Therapy
Extracellular Matrix
Plasmids
Up-Regulation
Cell Membrane

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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RNA interference-mediated simultaneous down-regulation of urokinase-type plasminogen activator receptor and cathepsin B induces caspase-8-mediated apoptosis in SNB19 human glioma cells. / Gondi, Christopher S.; Kandhukuri, Neelima; Kondraganti, Shakuntala; Gujrati, Meena; Olivero, William C.; Dinh, Dzung H.; Rao, Jasti S.

In: Molecular Cancer Therapeutics, Vol. 5, No. 12, 01.12.2006, p. 3197-3208.

Research output: Contribution to journalArticle

Gondi, Christopher S. ; Kandhukuri, Neelima ; Kondraganti, Shakuntala ; Gujrati, Meena ; Olivero, William C. ; Dinh, Dzung H. ; Rao, Jasti S. / RNA interference-mediated simultaneous down-regulation of urokinase-type plasminogen activator receptor and cathepsin B induces caspase-8-mediated apoptosis in SNB19 human glioma cells. In: Molecular Cancer Therapeutics. 2006 ; Vol. 5, No. 12. pp. 3197-3208.
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abstract = "The invasive character of gliomas depends on proteolytic cleavage of the surrounding extracellular matrix. Cathepsin B and urokinase-type plasminogen activator receptor (uPAR) together are known to be overexpressed in gliomas and, as such, are attractive targets for gene therapy. In the present study, we used plasmid constructs to induce the RNA interference (RNAi)-mediated down-regulation of uPAR and cathepsin B in SNB19 human glioma cells. We observed that the simultaneous down-regulation of uPAR and cathepsin B induces the up-regulation of proapoptotic genes and initiates a collapse in mitochondrial Δψ. Cathepsin B and uPAR down-regulated cells showed increases in the expression of activated caspase-8 and D FF40/caspase-activated DNase. Nuclear translocation of AIF and Fas ligand translocation to the cell membrane were also observed. Ki67 and X-linked inhibitor of apoptosis protein levels decreased, thereby indicating apoptosis. These results suggest the involvement of uPAR-cathepsin B complex on the cell surface and its role in maintaining the viability of SNB19 glioma cells. In conclusion, RNAi-mediated down-regulation of uPAR and cathepsin B initiates a partial extrinsic apoptotic cascade accompanied by the nuclear translocation of AIF. Our study shows the potential of RNAi-mediated down-regulation of uPAR and cathepsin B in developing new therapeutics for gliomas.",
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