| Title | Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. | | Author(s) | Li S, Rosenberg JE, Donjacour AA, Botchkina IL, Hom YK, Cunha GR, Blackburn EH | | Institution | Department of Biochemistry and Biophysics, University of California at San Francisco, San Francisco, CA 94143, USA. | | Source | Cancer Res 2004 Jul 15; 64(14):4833-40. | | MeSH | Animals
Apoptosis
Cell Division
Gene Therapy
Humans
Lentivirus
Male
Mice
Mice, Nude
RNA
RNA, Small Interfering
Rats
Telomerase
Telomere
Urinary Bladder Neoplasms
Xenograft Model Antitumor Assays
| | Abstract | In human cancers, telomeres are commonly maintained by elevated levels of the ribonucleoprotein enzyme telomerase, which contains an intrinsic templating RNA moiety (human telomerase RNA; hTER) and the core protein (human telomerase reverse transcriptase). We developed a lentiviral system for efficient overexpression of mutant-template human telomerase RNA (MT-hTer) to add mutant DNA to telomeres in cancer cells. We show that such MT-hTer overexpression rapidly inhibits cell growth and induces apoptosis in telomerase-positive precancerous or cancer cells but not in telomerase-negative cells. These rapid effects occurred independent of wild-type p53 and telomere length. Tumor growth and progression were significantly decreased in xenografts of human tumor cells overexpressing MT-hTers. Expression of a hairpin short-interfering RNA that specifically targeted the endogenous wild-type hTER template region, but spared the MT-hTers, also caused p53-independent cell growth inhibition and apoptosis, and when coexpressed with MT-hTer, synergistically killed cancer cells. Hence, anti-wild-type-hTER short-interfering RNA and MT-hTers may act through distinct pathways and, particularly in combination, represent a promising approach to anticancer therapies. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
| | PubMed ID | 15256453 |
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