Specific regulation of point-mutated K-ras-immortalized cell proliferation by a photodynamic antisense strategy.
It has been reported that point mutations in genes are responsible for various cancers, and the selective regulation of gene expression is an important factor in developing new types of anticancer drugs. To develop effective drugs for the regulation of point-mutated genes, we focused on photoreactive antisense oligonucleotides. Previously, we reported that photoreactive oligonucleotides containing 2'-O-psoralenylmethoxyethyl adenosine (2'-Ps-eom) showed drastic photoreactivity in a strictly sequence-specific manner. Here, we demonstrated the specific gene regulatory effects of 2'-Ps-eom on [(12)Val]K-ras mutant (GGT --> GTT). Photo-cross-linking between target mRNAs and 2'-Ps-eom was sequence-specific, and the effect was UVA irradiation-dependent. Furthermore, 2'-Ps-eom was able to inhibit K-ras-immortalized cell proliferation (K12V) but not Vco cells that have the wild-type K-ras gene. These results suggest that the 2'-Ps-eom will be a powerful nucleic acid drug to inhibit the expression of disease-causing point mutation genes, and has great therapeutic potential in the treatment of cancer.
Higuchi
Maiko
M
Department of Biomolecular Engineering, Kyoto Institute of Technology, Matsugasaki, Kyoto 606-8585, Japan.
Yamayoshi
Asako
A
Kato
Kiyoko
K
Kobori
Akio
A
Wake
Norio
N
Murakami
Akira
A
D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D017931:DNA Primers; D011905:Genes, ras; D051379:Mice; D041681:NIH 3T3 Cells; D010778:Photochemotherapy; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers