Alternative lengthening of telomeres in hTERT-inhibited laryngeal cancer cells
Alternative lengthening of telomeres in hTERT-inhibited laryngeal cancer cells
复制标题
hTERT 抑制的喉癌细胞中端粒的替代延长
DOI：
10.1111/j.1349-7006.2010.01611.x
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发表时间：
2010-08-01
期刊：
影响因子：
5.7
通讯作者：
Tao，Ze-Zhang
中科院分区：
文献类型：
--
作者：
Chen，Wei;Xiao，Bo-Kui;Tao，Ze-Zhang
在大多数人类恶性肿瘤中，端粒稳态是通过端粒酶的再激活来维持的。虽然抑制端粒酶为许多癌症的治疗提供了一种新的方法，但端粒维持可以在端粒酶活性不存在的情况下通过端粒（ALT）机制的替代延长而发生。因此，必须确定抑制端粒酶是否选择激活ALT的癌细胞。在这里，我们报告说，抗端粒酶治疗后存活的Hep-2细胞在培养中表现出持续增殖，人端粒酶逆转录酶（hTERT）表达下调，ALT特异性早幼粒细胞白血病（PML）小体水平显著升高。端粒延长动力学的分析也表明存活的Hep-2细胞中端粒姐妹染色单体交换（T-SCE）升高，与其长且异质的端粒一致。与ALT细胞相似，存活的细胞显示ALT端粒稳态的证据。此外，蛋白质组学分析确定了未处理的Hep-2细胞和存活细胞之间差异表达的几种蛋白质，这可能为理解这两种端粒维持机制提供新的见解。因此，这项研究的发现可能有助于改善基于端粒酶的癌症治疗。（Cancer Sci2010）
In most human malignancies, telomere homeostasis is maintained by the reactivation of telomerase. While inhibiting telomerase provides a novel approach to the treatment of many cancers, telomere maintenance can occur in the absence of telomerase activity by the alternative lengthening of telomeres (ALT) mechanism. Therefore, it must be determined if inhibiting telomerase selects for cancer cells that activate ALT. Here, we report that Hep‐2 cells that survived anti‐telomerase treatments showed sustained proliferation in culture with down‐regulated human telomerase reverse transcriptase (hTERT) expression and significantly enhanced levels of ALT‐specific promyelocytic leukemia (PML) bodies. Analysis of the telomere lengthening kinetics also demonstrated elevated telomeric sister‐chromatid exchange (T‐SCE) in surviving Hep‐2 cells, consistent with their long and heterogeneous telomeres. Similar to ALT cells, the surviving cells showed evidence of ALT telomere homeostasis. Furthermore, proteomic analysis identified several proteins differentially expressed between the untreated Hep‐2 cells and surviving cells that may provide new insight for understanding these two telomere maintenance mechanisms. Thus, the findings in this study may help to improve telomerase‐based therapy for cancer. (Cancer Sci2010)