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Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
Published on: April 13, 2015
A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation
M M Kim1, M A Rivera, I L Botchkina
1Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143-0448, USA.
Abstract:
The ribonucleoprotein telomerase synthesizes telomeric DNA by copying an intrinsic RNA template. In most cancer cells, telomerase is highly activated. Here we report a telomerase-based antitumor strategy: expression of mutant-template telomerase RNAs in human cancer cells. We expressed mutant-template human telomerase RNAs in prostate (LNCaP) and breast (MCF-7) cancer cell lines. Even a low threshold level of expression of telomerase RNA gene constructs containing various mutant templates, but not the control wild-type template, decreased cellular viability and increased apoptosis. This occurred despite the retention of normal levels of the endogenous wild-type telomerase RNA and endogenous wild-type telomerase activity and unaltered stable telomere lengths. In vivo tumor xenografts of a breast cancer cell line expressing a mutant-template telomerase RNA also had decreased growth rates. Therefore, mutant-template telomerase RNAs exert a strongly dominant-negative effect on cell proliferation and tumor growth. These results support the potential use of mutant-template telomerase RNA expression as an antineoplastic strategy.
Insights
Introducing a novel cancer therapy, this study shows that expressing mutant-template telomerase RNAs in cancer cells inhibits tumor growth and proliferation. This telomerase-based strategy offers a promising new avenue for cancer treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Telomerase is a ribonucleoprotein enzyme essential for synthesizing telomeric DNA.
- Telomerase activity is frequently upregulated in various cancer cells, contributing to their uncontrolled proliferation.
- Targeting telomerase presents a potential strategy for cancer therapy.
Purpose of the Study:
- To investigate the potential of expressing mutant-template telomerase RNAs as an antitumor strategy.
- To evaluate the effect of mutant-template telomerase RNA expression on cancer cell viability, apoptosis, and tumor growth.
Main Methods:
- Expression of mutant-template human telomerase RNAs in human prostate (LNCaP) and breast (MCF-7) cancer cell lines.
- Assessment of cellular viability and apoptosis following expression of mutant telomerase RNAs.
- Evaluation of tumor xenograft growth rates in vivo in mice bearing cancer cells expressing mutant telomerase RNA.
Main Results:
- Low-level expression of mutant-template telomerase RNAs, but not wild-type, significantly decreased cancer cell viability and increased apoptosis.
- These effects occurred independently of endogenous telomerase activity and telomere length.
- In vivo studies demonstrated reduced tumor growth rates in xenografts expressing mutant-template telomerase RNA.
Conclusions:
- Mutant-template telomerase RNAs exert a dominant-negative effect on cancer cell proliferation and tumor growth.
- This approach shows potential as a novel antineoplastic strategy.
- Further research into mutant-template telomerase RNA expression is warranted for cancer treatment development.
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