Telomerase inhibition, Telomere attrition and proliferation arrest of cancer cells induced by Phosphorothioate ASO-NLS conjugates targeting hTERC and siRNAs targeting hTERT

Diala, I; Shiohama, Y; Fujita, T; Demonacos, C; Krstic- Demonacos, M; Di Leva, G; Fujii, N

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.

Citation

Diala, I., Shiohama, Y., Fujita, T., Demonacos, C., Krstic- Demonacos, M., Di Leva, G., & Fujii, N. (2020). Telomerase inhibition, Telomere attrition and proliferation arrest of cancer cells induced by Phosphorothioate ASO-NLS conjugates targeting hTERC and siRNAs targeting hTERT. Nucleosides, Nucleotides and Nucleic Acids, 39(1-3), 407-425. https://doi.org/10.1080/15257770.2020.1713357

• Journal Article Type: Article
• Acceptance Date: Jan 5, 2020
• Online Publication Date: Apr 20, 2020
• Publication Date: Apr 20, 2020
• Deposit Date: Apr 24, 2020
• Publicly Available Date: Apr 20, 2021
• Journal: Nucleosides, Nucleotides & Nucleic Acids
• Print ISSN: 1525-7770
• Electronic ISSN: 1532-2335
• Publisher: Taylor and Francis
• Volume: 39
• Issue: 1-3
• Pages: 407-425
• DOI: https://doi.org/10.1080/15257770.2020.1713357
• Publisher URL: https://doi.org/10.1080/15257770.2020.1713357
• Related Public URLs: https://www.tandfonline.com/loi/lncn20
• Additional Information: Access Information : This is an Accepted Manuscript of an article published by Taylor & Francis in Nucleosides, Nucleotides & Nucleic Acids on 20th April 2020, available online: http://www.tandfonline.com/10.1080/15257770.2020.1713357; Funders : Japan Society for the Promotion of Science;KINDAI; Projects : Grant-in-Aid for Scientific Research;21st Century Joint Research Enhancement; Grant Number: (C) Nos. 22550159 and 25410182; Grant Number: KD1704 and KD14