Mutated telomeres sensitize tumor cells to anticancer drugs independently of telomere shortening and mechanisms of telomere maintenance
Mutated telomeres sensitize tumor cells to anticancer drugs independently of telomere shortening and mechanisms of telomere maintenance
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DOI：
10.1038/sj.onc.1209727
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发表时间：
2006-11-01
期刊：
影响因子：
8
通讯作者：
Autexier, C.
中科院分区：
文献类型：
--
作者：
Cerone, M. A.;Londono-Vallejo, J. A.;Autexier, C.
端粒酶是一种核糖核蛋白复合物，可维持染色体末端的稳定性并调节复制潜力。端粒酶在超过 85% 的人类肿瘤中表达上调，但在邻近的正常组织中却没有上调，是抗癌治疗的一个有希望的靶标。大多数基于端粒酶的疗法依赖于端粒酶活性的抑制，并且在诱导任何抗增殖作用之前需要广泛的端粒缩短。端粒结构的紊乱而不是长度的紊乱可能更有效地诱导细胞死亡。模板区域发生突变的端粒酶 RNA 亚基 (hTR) 可重构包含突变端粒序列的活性全酶。在这里，我们分析了基于端粒不稳定和常规化疗药物相结合的抗癌方法的可行性。我们发现，突变模板 hTR 决定了端粒酶阳性癌细胞中突变端粒重复序列的合成，而不会显着影响其活力和增殖能力。然而，突变的 hTR 增加了具有不同初始端粒长度和端粒维持机制的细胞对抗癌药物的敏感性，并且不需要整体端粒缩短。该报告首次表明，以端粒酶依赖性方式干扰端粒结构维持可用于增加肿瘤细胞对抗癌药物的敏感性，并可能导致开发出治疗人类癌症的通用疗法。
Telomerase is a ribonucleoprotein complex that maintains the stability of chromosome ends and regulates replicative potential. Telomerase is upregulated in over 85% of human tumors, but not in adjacent normal tissues and represents a promising target for anticancer therapy. Most telomerase-based therapies rely on the inhibition of telomerase activity and require extensive telomere shortening before inducing any antiproliferative effect. Disturbances of telomere structure rather than length may be more effective in inducing cell death. Telomerase RNA subunits (hTRs) with mutations in the template region reconstitute active holoenzymes that incorporate mutated telomeric sequences. Here, we analysed the feasibility of an anticancer approach based on the combination of telomere destabilization and conventional chemotherapeutic drugs. We show that a mutant template hTR dictates the synthesis of mutated telomeric repeats in telomerase-positive cancer cells, without significantly affecting their viability and proliferative ability. Nevertheless, the mutant hTR increased sensitivity to anticancer drugs in cells with different initial telomere lengths and mechanisms of telomere maintenance and without requiring overall telomere shortening. This report is the first to show that interfering with telomere structure maintenance in a telomerase-dependent manner may be used to increase the susceptibility of tumor cells to anticancer drugs and may lead to the development of a general therapy for the treatment of human cancers.