Telomere shortening and apoptosis in telomerase-inhibited human tumor cells

Despite a strong correlation between telomerase activity and malignancy, th e outcome of telomerase inhibition in human tumor cells has not been examin ed. Here, we have addressed the role of telomerase activity in the prolifer ation of human tumor and immortal cells by inhibiting TERT function. Induci ble dominant-negative mutants of hTERT dramatically reduced the level of en dogenous telomerase activity in tumor cell lines. Clones with short telomer es continued to divide, then exhibited an increase in abnormal mitoses foll owed by massive apoptosis leading to the loss of the entire population. Thi s cell death was telomere-length dependent, as cells with long telomeres we re viable but exhibited telomere shortening at a rate similar to that of mo rtal cells. It appears that telomerase inhibition in cells with short telom eres lead to chromosomal damage, which in turn trigger apoptotic cell death . These results provide the first direct evidence that telomerase is requir ed for the maintenance of human tumor and immortal cell viability, and sugg est that tumors with short telomeres may be effectively and rapidly killed following telomerase inhibition.