Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation
Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation
复制标题
蒽环类药物通过诱导 PinX1 泛素化和降解来破坏端粒酶对端粒的维持
DOI：
10.1038/onc.2011.214
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发表时间：
2012-01-01
期刊：
影响因子：
8
通讯作者：
Huang, J-J
中科院分区：
文献类型：
--
作者：
Zhang, B.;Qian, D.;Huang, J-J
端粒的维持对癌症的生长至关重要。例如，通过抑制端粒蛋白或端粒酶来诱导端粒功能障碍，已被证明可以强烈增强癌细胞对化疗的敏感性。然而，尚不清楚端粒维持的调节是否构成癌细胞对化疗的反应。此外，抗癌药物影响端粒功能的方式仍然未知。在本研究中，我们发现蒽环类药物作为一类广泛应用于临床癌症治疗的抗癌药物，在端粒酶阳性的癌细胞中特异性地触发端粒功能障碍中具有积极作用。蒽环类药物通过下调PinX1来中断端粒酶对端粒的维持，PinX1是一种负责将端粒酶靶向到端粒上的蛋白质因子，从而抑制端粒酶与端粒的关联。我们进一步证明，蒽环类药物通过泛素-蛋白酶体依赖途径诱导PinX1蛋白降解，从而下调PinX1蛋白的表达。我们的研究结果不仅揭示了蒽环类药物作为端粒酶功能抑制剂的新作用，而且为基于端粒酶/端粒靶向的新型抗癌药物的开发提供了线索，目前许多研究正在积极探索。中国癌症杂志（2012）31,1-12；doi: 10.1038 / onc.2011.214;2011年6月6日在线发布
Telomere maintenance is essential for cancer growth. Induction of telomere dysfunction, for example, by inhibition of telomeric proteins or telomerase, has been shown to strongly enhance cancer cells' sensitivity to chemotherapies. However, it is not clear whether modulations of telomere maintenance constitute cancer cellular responses to chemotherapies. Furthermore, the manner in which anti-cancer drugs affect telomere function remains unknown. In this study, we show that anthracyclines, a class of anti-cancer drugs widely used in clinical cancer treatments, have an active role in triggering telomere dysfunction specifically in telomerase-positive cancer cells. Anthracyclines interrupt telomere maintenance by telomerase through the down-regulation of PinX1, a protein factor responsible for targeting telomerase onto telomeres, thereby inhibiting telomerase association with telomeres. We further demonstrate that anthracyclines downregulate PinX1 by inducing this protein degradation through the ubiquitin-proteasome-dependent pathway. Our data not only reveal a novel action for anthracyclines as telomerase functional inhibitors but also provide a clue for the development of novel anti-cancer drugs based on telomerase/telomere targeting, which is actively investigated by many current studies. Oncogene (2012) 31, 1-12; doi: 10.1038/onc.2011.214; published online 6 June 2011