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Ribozyme cleavage of telomerase mRNA sensitizes breast epithelial cells to inhibitors of topoisomerase

Lookup NU author(s): Dr Gabriele Saretzki, Professor Thomas von Zglinicki

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Abstract

Telomerase activity is necessary and sufficient for immortality in many cells and hence represents a prime target for antitumor strategies. Here, we show that a hammerhead ribozyme cleaves human telomerase (hTERT) mRNA in vitro, Stable transfection in clones of the human breast tumor line MCF-7 and the immortal breast cell line HBL-100 results in expression of the ribozyme, diminishes the abundance of hTERT mRNA, and inhibits telomerase activity. This led to shortened telomeres, inhibition of net growth, and induction of apoptosis. In HBL-100 mass cultures infected with a ribozyme-expressing adenovirus diminution of hTERT mRNA, attenuation of telomerase activity, inhibition of net growth, and induction of apoptosis was found as well. Attenuation of telomerase activity increased the sensitivity of HBL-100 and MCF-7 clones specifically to inhibitors of topoisomerase, Likewise, expression of exogenous telomerase in originally telomerase-negative human fibroblasts decreased their sensitivity to topoisomerase poisons but not to a number of other cytotoxic drugs. The data validate a ribozyme approach for telomerase inhibition therapy in canter and suggest that it might be combined advantageously with topoisomerase-directed chemotherapy.


Publication metadata

Author(s): Saretzki G; von Zglinicki T; Ludwig A; Holm PS; Tiemann F; Lorenz M; Emrich T; Harley CB

Publication type: Article

Publication status: Published

Journal: Cancer Research

Year: 2001

Volume: 61

Issue: 7

Pages: 3053-3061

ISSN (print): 0008-5472

ISSN (electronic): 1538-7445

Publisher: American Association for Cancer Research

URL: http://cancerres.aacrjournals.org/content/61/7/3053.full


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