Telomerase inhibition by siRNA causes senescence and apoptosis in Barrett's adenocarcinoma cells: mechanism and therapeutic potential.
Telomerase inhibition by siRNA causes senescence and apoptosis in Barrett's adenocarcinoma cells: mechanism and therapeutic potential.
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DOI：
10.1186/1476-4598-4-24
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发表时间：
2005-07-15
期刊：
影响因子：
37.3
通讯作者：
Goyal RK
中科院分区：
文献类型：
--
作者：
Shammas MA;Koley H;Batchu RB;Bertheau RC;Protopopov A;Munshi NC;Goyal RK
在癌细胞中，端粒酶诱导有助于维持端粒长度，从而绕过衰老，增强复制潜力。端粒酶的化学抑制剂已被证明可以重新激活端粒缩短，引起肿瘤细胞的复制性衰老和凋亡细胞死亡，而对正常二倍体细胞几乎没有或没有影响。我们针对端粒酶基因的两个不同区域设计了sirna，并评估了它们对Barrett腺癌SEG-1细胞端粒长度、增殖潜力和基因表达的影响。纳米摩尔浓度的sirna混合物导致端粒酶活性的丧失，这种丧失早在第1天出现，并在第3天基本完成。在超过50%的处理细胞中，端粒酶活性的抑制与中位端粒长度的显著减少和可检测端粒的完全丢失有关。端粒丢失导致40%的处理细胞衰老，86%的处理细胞凋亡。这些反应似乎与DNA传感器HR23B的激活以及随后p53同源物p73、p63和E2F1的激活有关。这些基因调节因子的变化可能是观察到的细胞周期抑制剂p16和GADD45上调的来源。还观察到激活死亡受体的FasL、Fas和caspase 8转录水平升高，以及与Bcl10和NFKB相互作用以增强线粒体易位和caspase 9激活的CARD 9转录水平升高。这些研究表明，端粒酶sirna可以有效抑制端粒酶和端粒缩短，从而导致细胞周期阻滞和细胞凋亡，其机制包括上调参与细胞周期阻滞和细胞凋亡的几个基因。因此，端粒酶sirna可能是巴雷特腺癌化学预防和治疗的高选择性治疗的强有力的候选者。
In cancer cells, telomerase induction helps maintain telomere length and thereby bypasses senescence and provides enhanced replicative potential. Chemical inhibitors of telomerase have been shown to reactivate telomere shortening and cause replicative senescence and apoptotic cell death of tumor cells while having little or no effect on normal diploid cells. We designed siRNAs against two different regions of telomerase gene and evaluated their effect on telomere length, proliferative potential, and gene expression in Barrett's adenocarcinoma SEG-1 cells. The mixture of siRNAs in nanomolar concentrations caused a loss of telomerase activity that appeared as early as day 1 and was essentially complete at day 3. Inhibition of telomerase activity was associated with marked reduction in median telomere length and complete loss of detectable telomeres in more than 50% of the treated cells. Telomere loss caused senescence in 40% and apoptosis in 86% of the treated cells. These responses appeared to be associated with activation of DNA sensor HR23B and subsequent activation of p53 homolog p73 and p63 and E2F1. Changes in these gene regulators were probably the source of observed up-regulation of cell cycle inhibitors, p16 and GADD45. Elevated transcript levels of FasL, Fas and caspase 8 that activate death receptors and CARD 9 that interacts with Bcl10 and NFKB to enhance mitochondrial translocation and activation of caspase 9 were also observed. These studies show that telomerase siRNAs can cause effective suppression of telomerase and telomere shortening leading to both cell cycle arrest and apoptosis via mechanisms that include up-regulation of several genes involved in cell cycle arrest and apoptosis. Telomerase siRNAs may therefore be strong candidates for highly selective therapy for chemoprevention and treatment of Barrett's adenocarcinoma.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
4.8
作者：
Bertin, J;Guo, Y;Alnemri, ES
通讯作者：
Alnemri, ES
影响因子：
3.5
作者：
Lansdorp, PM;Verwoerd, NP;Tanke, HJ
通讯作者：
Tanke, HJ
影响因子：
64.8
作者：
HARLEY, CB;FUTCHER, AB;GREIDER, CW
通讯作者：
GREIDER, CW