Differences in telomerase activity and the effects of AZT in aneuploid and euploid cells in colon cancer.

Abstract

Telomerase-targeted treatments for cancer have received a great deal of attention because telomerase is detected in nearly all cancer cells but is not expressed in most normal tissues. Aneuploidy refers to a chromosome number that is not a multiple of the base chromosome number and can indicate either hypo- or hyperploid chromosome numbers. Most solid tumors are aneuploid. In the present study, we sought to determine whether there are differences in telomerase activity and hTERT gene expression between aneuploid and euploid cells. Furthermore, we investigated telomerase inhibitor 3'-azido-3'-deoxythymidine (AZT)-induced cell apoptosis using the p53-Puma/Noxa/Bax pathway and cell cycle arrest using the p53-p21 pathway in both aneuploid and euploid cells. Our results demonstrate that telomerase activity and hTERT gene expression were higher in aneuploid than in euploid cells. In addition, AZT exerted time- and dose-dependent cytotoxic effects on both aneuploid and euploid cells, and aneuploid cells were more sensitive to AZT-induced cytotoxicity. In addition, both the p53-Puma/Noxa/Bax pathway and the cell cycle arrest-associated p53-p21 pathway were involved in the AZT-induced suppression of tumor cells. Importantly, aneuploid cells were more sensitive to AZT-induced cell cycle arrest (p53-p21) and DNA double-strand breaks (γ-H2AX), while euploid cells were more sensitive to AZT-induced apoptosis (p53-Puma/Bax/Noxa).