Telomerase inhibition by stable RNA interference impairs tumor growth and angiogenesis in glioblastoma xenografts

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Abstract

Telomerase is highly expressed in advanced stages of most cancers where it allows the clonal expansion of transformed cells by counteracting telomere erosion. Telomerase may also contribute to tumor progression through still undefined cell growth-promoting functions. Here, we inhibited telomerase activity in 2 human glioblastoma (GBM) cell lines, TB10 and U87MG, by targeting the catalytic subunit, hTERT,viastable RNA interference (RNAi). Although the reduction in telomerase activity had no effect on GBM cell growthin vitro, the development of tumors in subcutaneously and intracranially grafted nude mice was significantly inhibited by antitelomerase RNAi. Thein vivoeffect was observed within a relatively small number of population doublings, suggesting that telomerase inhibition may hinder cancer cell growthin vivoprior to a substantial shortening of telomere length. Tumor xenografts that arose from telomerase-inhibited GBM cells also showed a less-malignant phenotype due both to the absence of massive necrosis and to reduced angiogenesis.

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