Telomerase Reverse Transcriptase (hTERT) mRNA and Telomerase RNA (hTR) as Targets for Downregulation of Telomerase Activity

Telomerase is expressed in cancer cells but not in most normal cells, leading to the hypothesis that telomerase inhibitors may be a powerful approach to cancer therapy. It is possible that telomerase plays roles in the cell other than telomere elongation and that blocking telomerase expression may have consequences that differ from simply blocking the active site through competitive inhibition. Here, we test this hypothesis by comparing the effects of antisense oligonucleotides and small interfering RNAs (siRNAs) that target the telomerase reverse transcriptase (hTERT) mRNA with the effects of oligonucleotides that target the telomerase RNA component (hTR). We find that the use of anti-hTR oligomers is more effective in blocking telomerase expression than strategies that target hTERT mRNA. Anti-hTR compounds are active on addition to cells in the absence of lipid, whereas antisense oligonucleotides are not. The modest inhibition of hTERT expression caused by antisense oligonucleotides or siRNAs does not persist, suggesting development of resistance. These data suggest that strategies for telomerase inhibition that require downregulation of hTERT mRNA may be less straightforward than those that target hTR. In addition, we have not seen evidence for a role for hTERT other than in telomere maintenance.