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 driver genes, in a sequence specific fashion to down-regulate the expression of the target gene. The protein catalytic subunit, human telomerase reverse transcriptase (hTERT) and the template RNA component (hTERC) are essential for telomerase function, thus theoretically, inhibition of telomerase activity can be achieved by interfering with either the gene expression of hTERT or the hTERC of the telomerase enzymatic complex. The present study showed that phosphorothioate antisense oligonucleotide (sASO)-nuclear localization signal (NLS) peptide conjugates targeting hTERC could inhibit telomerase activity very efficiently at 5 μM concentration but less efficiently at 1 μM concentration. On the other hand, siRNA targeting hTERT mRNA could strongly suppress hTERT expression at 200 nM concentration. It was also revealed that siRNA targeting hTERT could induce telomere attrition and then irreversible arrest of proliferation of cancer cells.

中文翻译：

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靶向 hTERC 的硫代磷酸酯 ASO-NLS 偶联物和靶向 hTERT 的 siRNA 诱导癌细胞的端粒酶抑制、端粒磨损和增殖停滞

摘要 端粒酶活性被认为是细胞永生化和致癌作用的关键步骤，因此，端粒酶的调节代表了抗肿瘤特异性治疗的一个有吸引力的目标。最近，癌症研究的一个途径集中在反义策略以靶向癌基因或癌症驱动基因，以序列特异性方式下调靶基因的表达。蛋白质催化亚基、人端粒酶逆转录酶 (hTERT) 和模板 RNA 组分 (hTERC) 对端粒酶功能至关重要，因此理论上，可以通过干扰 hTERT 的基因表达或 hTERC 的基因表达来抑制端粒酶活性。端粒酶复合物。本研究表明，靶向 hTERC 的硫代磷酸酯反义寡核苷酸 (sASO)-核定位信号 (NLS) 肽缀合物可以在 5 μM 浓度下非常有效地抑制端粒酶活性，但在 1 μM 浓度下效果较差。另一方面，靶向 hTERT mRNA 的 siRNA 在 200 nM 浓度下可以强烈抑制 hTERT 表达。还发现靶向 hTERT 的 siRNA 可以诱导端粒磨损，然后不可逆地阻止癌细胞的增殖。