Nature Biotechnology20, 895 - 900 (2002)
Published online: 19 August 2002; | doi:10.1038/nbt730
Inhibition of glioma growth by tumor-specific activation of
double-stranded RNA−dependent protein kinase PKR
Alexei Shir
& Alexander Levitzki
Unit of Cellular Signaling, Department of
Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The
Hebrew University of Jerusalem, Givat Ram, Jerusalem
91904, Israel.
Activated double-stranded RNA (dsRNA)−dependent protein kinase
PKR is a potent growth inhibitory protein that is primarily activated in
virally infected cells, inducing cell death. Here we investigate whether
selective activation of PKR can be used to kill cancer cells that express
mutated genes containing deletions or chromosomal translocations. We show that
antisense (AS) RNA complementary to fragments flanking the deletion or
translocation can produce a dsRNA molecule of sufficient length to activate PKR
and induce cell death following hybridization with mutated but not wild-type
mRNA. Using the U87MGEGFR cell line, which expresses a truncated form of
epidermal growth factor receptor (EGFR), (2-7) EGFR, we found that
expression of a 39-nucleotide (nt) AS RNA complementary to the unique exon 1 to
8 junction caused selective death of cells harboring the truncated EGFR both
in vitro and in vivo but did not affect cells expressing
wild-type EGFR. A lentiviral vector expressing the 39-nt AS sequence strongly
inhibited glioblastoma growth in mouse brain when injected after tumor cell
implantation. This PKR-mediated killing strategy may be useful in treating many
cancers that express a unique RNA species.
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