Down-regulation of human telomerase reverse transcriptase through specific activation of RNAi pathway quickly results in cancer cell growth impairment

Paolo Gandellini, Marco Folini, Roberto Bandiera, Michelandrea De Cesare, Mara Binda, Silvio Veronese, Maria Grazia Daidone, Franco Zunino, Nadia Zaffaroni

Research output: Contribution to journalArticle

Abstract

Targeting of human telomerase reverse transcriptase (hTERT) by different small interfering RNAs (siRNAs) resulted in a variable degree of telomerase activity inhibition in PC-3 and DU145 prostate cancer cells. In addition, transfection with siRNA5 and siRNA41, which caused high levels (∼80 and ∼55%, respectively) of enzyme activity inhibition in both cell lines, led to a marked reduction of hTERT mRNA and protein expression and a significant inhibition of cell proliferation within a few days, without concomitant telomere shortening or telomeric 3′ overhang impairment. Such an antiproliferative effect was not ascribable to the activation of non-specific responses, since siRNA5 and siRNA41 did not induce the expression of 2′-5′ oligoadenylate synthetase-1 and were able to cause a significant growth impairment also in HCT 116 colon cancer cells, which have a defective interferon pathway. Cell growth inhibition was indeed associated with hTERT down-regulation, as it was almost completely rescued in siRNA-treated HCT 116 cells co-transfected with an hTERT-expressing vector. Moreover, siRNA5 and siRNA41 failed to affect the proliferation of hTERT-negative U2-OS osteosarcoma cells. Interestingly, transfection with siRNA5 significantly reduced the tumorigenic and growth potential of PC-3 cells when xenotransplanted into nude mice. Such data suggest siRNA-mediated hTERT down-regulation as an efficient strategy to impair prostate cancer cell growth.

Original languageEnglish
Pages (from-to)1703-1714
Number of pages12
JournalBiochemical Pharmacology
Volume73
Issue number11
DOIs
Publication statusPublished - Jun 1 2007

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Keywords

  • Cell growth
  • hTERT
  • Prostate cancer
  • RNA interference
  • Small interfering RNA
  • Telomerase

ASJC Scopus subject areas

  • Pharmacology

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