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
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
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DOI：
10.1016/j.ejca.2004.12.002
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发表时间：
2005-03-01
影响因子：
8.4
通讯作者：
Zaffaroni, N
中科院分区：
文献类型：
--
作者：
Folini, M;Brambilla, C;Zaffaroni, N
最近的证据表明，人类端粒酶逆转录酶（hTERT）在促进肿瘤细胞存活方面具有一种新的功能，这种功能可能独立于酶的端粒延长活性。为了验证这一假设，我们通过反义寡核苷酸介导的对hTERT或人类端粒酶RNA成分（hTERC）的干扰来比较端粒酶抑制对DU145人前列腺癌细胞增殖潜力的影响。将细胞暴露于针对hTERT pre-mRNA剪接位点的2'- o -甲基rna硫代寡核苷酸中，由于hTERT mRNA表达水平显著降低，DU145细胞生长早期下降和凋亡细胞死亡，而端粒没有明显缩短，从而导致端粒酶活性几乎完全抑制。相反，将DU145细胞暴露于靶向hTERC模板区的2'- o -甲基rna硫代寡核苷酸中，尽管端粒酶活性几乎完全消失，但未能干扰细胞增殖。这些结果扩展并证实了早期支持hTERT维持肿瘤细胞存活和增殖的酶活性独立机制的证据。(c) 2004 Elsevier Ltd.版权所有。
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. (c) 2004 Elsevier Ltd. All rights reserved.