〈PAPER〉Suppression of Telomerase Activity and Proliferation of Human Cancer Cells by anti-hTERT siRNAs and anti-hTR S-OligoDNA-Signal Peptide Conjugates
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[和文要約] テロメラーゼ（ｈTERT）はヒト染色体のテロメアを伸長する逆転写酵素であり、癌細胞に特有に発現するため癌治療の格好の標的と目されている。テロメラーゼｍRNAを標的とするsiRNAとテロメラーゼテンプレートRNA（ｈTR）を標的とするホスホロチオエートDNA（S-DNA)-シグナルペプチドコンジュゲートを用いて、ヒト癌細胞に発現するテロメラーゼ活性を阻害し、その増殖を抑制することに成功した。また、ホスホロチオエートＤＮＡ（Ｓ-ＤＮＡ）と核局在化シグナル（ＮＬＳ）ペプチドとのコンジュゲートは遺伝子導入剤を用いることなく細胞内に侵入し、標的であるテロメラーゼが存在している核内局在化することを証明した。 [Abstract] Telomerase activity has been regarded as a critical step in cellular immortalization and carcinogenesis and because of this, regulation of telomerase represents an attractive target for anti-tumor specific therapeutics. Recently, one avenue of cancer research focuses on antisense strategy to target the oncogenes or cancer causing genes, in a specific fashion to completely inhibit the expression of the target gene. The protein catalytic sub-unit, human telomerase reverse transcriptase, hTERT and the template RNA, hTR are essential for telomerase function, thus theoretically, inhibition of telomerase activity can be achieved by interfering with either the hTR or hTERT component of telomerase enzymatic complex. This study made use of antisense strategy to compare effects of small interfering RNAs (siRNAs) that targets the telomerase reverse transcriptase hTERT mRNA with the effect of synthesized phosphorothioate oligonucleotide-peptide conjugates that targets the RNA component hTR in inhibiting telomerase activity. Based from the results of this study, both antisense approaches have successfully suppressed telomerase activity but of varying levels of inhibition. Several factors have been identified that may have caused such variation in the level of telomerase inhibition. For siRNA strategy, 6 siRNA sequences directed at different sites of the hTERT gene were screened using quantitative RT-PCR before choosing the best siRNA sequence that was to be use to determine effect on the inhibition of telomerase activity. While for the antisense approach that targets the hTR component of the enzyme, the covalent coupling of signal peptide with the oligonucleotide enhances the inhibitory effect of the conjugate to telomerase activity. Overall, the study was able to show the specificity of antisense strategy to inhibit telomerase activity.
- 2011-07-00
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- 〈PAPER〉Suppression of Telomerase Activity and Proliferation of Human Cancer Cells by anti-hTERT siRNAs and anti-hTR S-OligoDNA-Signal Peptide Conjugates