Telomerase activation plays critical roles in
tumor growth and progression in part through the maintenance of telomere structure. Indeed, the ubiquitous expression of
telomerase in human
cancers makes
telomerase a promising target for
cancer therapy. Genetic, pharmacologic, and antisense methods to inhibit
telomerase have been described; however, in most cases,
cancer cell death was observed only after many cell divisions. Here, using retroviral delivery of small interfering RNAs (siRNAs) specific for the human
telomerase reverse transcriptase (hTERT), we successfully inhibited
telomerase activity in
cervical cancer cell lines. Cells lacking hTERT expression exhibited significantly decreased
telomerase activity and showed shortened telomeres and telomeric 3' overhangs with passage. These cells entered replicative senescence after a considerable number of cell divisions. Notably, the proliferative rate of these cells was significantly impaired, compared with control cells with
telomerase activity, even in low-passage cells (population doubling 5). Likewise, colony-forming ability and tumorigenicity in mice were attenuated in low-passage cells lacking hTERT. We further examined the effects of
chemotherapy and ionizing radiation on cells in which hTERT expression was suppressed. Cells lacking hTERT showed a significantly increased sensitivity, compared with control cells, to ionizing radiation or chemotherapeutic agents that induce
DNA double- strand breaks, such as
topoisomerase inhibitors or
bleomycin. These findings suggest that an
siRNA-based strategy can be applied to the development of novel
telomerase inhibitors, the antitumor effects of which may be enhanced in combination with ionizing radiation and
chemotherapy.