Mechanism of Telomerase Inhibition Using Small Inibitory RNAs and Induction of Breast Tumor Cell Sensitivity

摘要

Telomerase, a ribonucleoprotein enzyme composed of an RNA template (hTR) and a catalytically active protein subunit (hTERT), synthesizes telomeres after cell divisions and is obligatory for continuous tumor cell proliferation as well as malignant progression of breast cancer cells. Telomerase is an attractive anti-cancer therapeutic agent because telomerase activity is present in over 90% of human breast cancers but is undetectable in most normal somatic cells. Traditional therapies (surgery, chemotherapy, radiotherapy, etc.) lack the ability to effectively control and cure breast cancer, primarily because residual cells are or become resistant to DNA damaging modalities including standard chemo- and radio-therapies. Since telomerase requires its associated hTR for repeat synthesis, we have chosen to use RNA interference as a method to inactivate hTR and hence telomerase. RNA interference (RNAi) has become a powerful tool for the analysis of gene function in that RNAi allows sequence specific inhibition of gene expression. Another protein we targeted is p21, which has long been established as a requirement for senescence. We wanted to further examine its relationship to senescence and apotosis, in an attempt to sensitize breast tumor cells more effectively.