A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation

The ribonucleoprotein telomerase synthesizes telomeric DNA by copying an in trinsic 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-templa te human telomerase RNAs in prostate (LNCaP) and breast (MCF-7) cancer cell lines. Even a low threshold level of expression of telomerase RNA gene con structs containing various mutant templates, but not the control wild-type template, decreased cellular viability and increased apoptosis. This occurr ed despite the retention of normal levels of the endogenous wild-type telom erase RNA and endogenous wildtype telomerase activity and unaltered stable telomere lengths. In vivo tumor xenografts of a breast cancer cell line exp ressing a mutant-template telomerase RNA also had decreased growth rates, T herefore, mutant-template telomerase RNAs exert a strongly dominant-negativ e effect on cell proliferation and tumor growth. These results support the potential use of mutant-template telomerase RNA expression as an antineopla stic strategy.