title: Down-regulation of human telomerase reverse transcriptase through specific activation of RNAi pathway quickly results in cancer cell growth impairment.
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 ( approximately 80 and approximately 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.
authors.affiliation: Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gandellini
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
authors.forename: Roberto
authors.initials: R
authors.lastname: Bandiera
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Mara
authors.initials: M
authors.lastname: Binda
authors.forename: Silvio
authors.initials: S
authors.lastname: Veronese
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Daidone
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016615:Telomere / Q000187:drug effects / Q000201:enzymology; D014407:Tumor Cells, Cultured
chemical_list: D034741:RNA, Small Interfering; C509186:TERT protein, human; D019098:Telomerase