Inhibition of telomerase is related to the life span and tumorigenicity ofhuman prostate cancer cells

Purpose: Telomerase, the enzyme that catalyzes the elongation of telomeres, is illegitimately activated in the majority of cancers, including that of the prostate, where it may greatly extend the life span of malignant cells. The inhibition of telomerase by molecular intervention has been shown to l ead eventually to cell death in several tumor or in vitro immortalized cell lines and in 1 case prevent tumor growth in vivo. Therefore, we tested whe ther a similar strategy may be used to limit the tumorigenic potential of l ate stage prostate cancer cells. Materials and Methods: PC-3, LNCaP and DU-145 human prostate cancer cells w ere infected with a retrovirus encoding a dominant-negative version of the catalytic subunit of telomerase (DN-hTERT). Subclones or polyclonal populat ions were assayed for DN-hTERT expression, telomerase activity, telomere le ngth, cell life span and in most cases tumorigenicity in nude mice. Results: DN-hTERT expression levels directly correlated with cell life span and tumorigenic growth. PC-3 cells expressing high levels of DN-hTERT died rapidly and failed to form tumors in nude mice, whereas cells expressing t he lowest levels proliferated the longest and generated tumors that later s pontaneously regressed. Similarly the inhibition of telomerase activity in LNCaP cells was greater than in DU-145 cells and correspondingly LNCaP cell s had a shorter life span. Conclusions: DN-hTERT expression limits the life span and tumorigenic poten tial of human prostate cancer cells, although the onset of these effects ap pears to be dictated by the expression level of DN-hTERT. Therefore, telome rase represents an attractive target for potentially managing prostate canc er. Nevertheless, effective means of inhibiting the enzyme may be required for a therapeutically useful outcome.