Oligomer-mediated modulation of hTERT alternative splicing induces telomerase inhibition and cell growth decline in human prostate cancer cells

C. Brambilla, M. Folini, P. Gandellini, L. Daprai, M. G. Daidone, N. Zaffaroni

Research output: Contribution to journalArticle

Abstract

The expression of telomerase in human cells is strictly controlled by multiple mechanisms including transcription and alternative splicing of telomerase reverse transcriptase (hTERT). In this study, we demonstrated the possibility of modulating the hTERT splicing pattern in DU145 human prostate carcinoma cells through the use of 2′-O-methyl-RNA phosphorothioate oligonucleotides targeting the splicing site located between intron 5 and exon 6 in the hTERT pre-mRNA. An 18-h oligonucleotide exposure induced a decrease in the full-length hTERT transcript and a concomitant increase in the alternatively spliced transcripts, which resulted in significant inhibition of telomerase catalytic activity. Moreover, exposure to the R7 oligomer (which induced the most pronounced modulation of the hTERT splicing pattern and the greatest telomerase inhibition) caused a marked reduction in DU145 cell growth and the induction of apoptosis starting 2 days after treatment. Such data support the concept that down-regulation of hTERT expression can cause short-term effects on tumour cell growth, which are telomere-shortening independent.

Original languageEnglish
Pages (from-to)1764-1774
Number of pages11
JournalCellular and Molecular Life Sciences
Volume61
Issue number14
Publication statusPublished - Jul 2004

Keywords

  • 2′-O-methyl phosphorothioate oligoribonucleotide
  • Alternative splicing
  • Apoptosis
  • DU145 prostate cancer cell line
  • hTERT catalytic subunit

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Cell Biology

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