title: Antisense oligonucleotide-mediated inhibition of hTERT, but not hTERC, induces rapid cell growth decline and apoptosis in the absence of telomere shortening in human prostate cancer cells.
abstract: Recent evidence points to a novel function of human telomerase reverse transcriptase (hTERT) in promoting tumour cell survival, which might be independent of the telomere-elongating activity of the enzyme. To test this hypothesis, we evaluated comparatively the effects of telomerase inhibition, accomplished through antisense oligonucleotide-mediated interference with hTERT or human telomerase RNA component (hTERC), on the proliferative potential of DU145 human prostate cancer cells. Exposure of cells to a 2'-O-methyl-RNA phosphorothioate oligonucleotide targeting a splicing site within hTERT pre-mRNA induced almost complete inhibition of telomerase activity as a consequence of a marked reduction of the hTERT mRNA expression level, an early decline of DU145 cell growth and apoptotic cell death without any appreciable telomere shortening. Conversely, exposure of DU145 cells to a 2'-O-methyl-RNA phosphorothioate oligonucleotide targeting the template region of hTERC failed to interfere with cell proliferation in spite of the almost complete abrogation of telomerase activity. These results extend and corroborate earlier evidence in favour of an enzymatic activity-independent mechanism by which hTERT maintains tumour cell survival and proliferation.
authors.affiliation: Dipartimento di Oncologia Sperimentale, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
authors.forename: Cinzia
authors.initials: C
authors.lastname: Brambilla
authors.forename: Raffaella
authors.initials: R
authors.lastname: Villa
authors.forename: Paolo
authors.initials: P
authors.lastname: Gandellini
authors.forename: Sara
authors.initials: S
authors.lastname: Vignati
authors.forename: Francesco
authors.initials: F
authors.lastname: Paduano
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Daidone
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D017209:Apoptosis; D002455:Cell Division; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D006801:Humans; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D019098:Telomerase