PNA-mediated modulation and redirection of Her-2 pre-mRNA splicing: specific skipping of erbB-2 exon 19 coding for the ATP catalytic domain

TY - JOUR

T1 - PNA-mediated modulation and redirection of Her-2 pre-mRNA splicing: specific skipping of erbB-2 exon 19 coding for the ATP catalytic domain

AU - Pankratova, Stanislava

AU - Nielsen, Birgit N

AU - Shiraishi, Takehiko

AU - Nielsen, Peter E

PY - 2010/1

Y1 - 2010/1

N2 - The Her-2 receptor coded for by the proto-oncogenic erbB-2 gene is a clinically validated target for treatment of a significant genetic subclass of breast cancers, and Her-2 is also overexpressed or mutated in a range of other cancers. In an approach to exploit antisense mediated splicing interference as a means of manipulating erbB-2 expression in a therapeutically relevant fashion, we have studied the effect on mRNA splicing of a series of peptide nucleic acid (PNA) oligomers targeting specific intron-exon junctions in the erbB-2 pre-mRNA. In particular, we are interested in identifying PNA oligomers that specifically induce skipping of exon 19 as this exon is coding for the ATP catalytic domain of Her-2, and if expressed such truncated version of the Her-2 protein should be functionally inactive in a dominant negative fashion. Therefore, antisense compounds having efficient erbB-2 exon 19 skipping activity could be very interesting in terms of drug discovery. In the present study we identified PNA oligomers having such activity in SK-BR-3 and HeLa cancer cells in culture.

AB - The Her-2 receptor coded for by the proto-oncogenic erbB-2 gene is a clinically validated target for treatment of a significant genetic subclass of breast cancers, and Her-2 is also overexpressed or mutated in a range of other cancers. In an approach to exploit antisense mediated splicing interference as a means of manipulating erbB-2 expression in a therapeutically relevant fashion, we have studied the effect on mRNA splicing of a series of peptide nucleic acid (PNA) oligomers targeting specific intron-exon junctions in the erbB-2 pre-mRNA. In particular, we are interested in identifying PNA oligomers that specifically induce skipping of exon 19 as this exon is coding for the ATP catalytic domain of Her-2, and if expressed such truncated version of the Her-2 protein should be functionally inactive in a dominant negative fashion. Therefore, antisense compounds having efficient erbB-2 exon 19 skipping activity could be very interesting in terms of drug discovery. In the present study we identified PNA oligomers having such activity in SK-BR-3 and HeLa cancer cells in culture.

U2 - 10.3892/ijo_00000472

DO - 10.3892/ijo_00000472

M3 - Journal article

C2 - 19956830

SN - 1019-6439

VL - 36

SP - 29

EP - 38

JO - International Journal of Oncology

JF - International Journal of Oncology

IS - 1

ER -