G-quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells
G-quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells
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DOI：
10.1038/sj.onc.1209217
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发表时间：
2006-03-23
期刊：
影响因子：
8
通讯作者：
Ide, T
中科院分区：
文献类型：
--
作者：
Tahara, H;Shin-ya, K;Ide, T
端粒酶抑制剂抑制端粒酶活性，导致端粒逐渐丧失，进而导致癌细胞进入危机阶段。在这里，我们报道了端粒酶抑制剂telomestatin，已知它可以稳定30个单链端粒突出端（G尾）的G四链体结构，当以不会导致正常细胞死亡的浓度给药时，它可以在一周内迅速将TRF2从癌细胞的端粒上解离。使用该药物短期治疗后，癌细胞系中的 G 尾显着减少，但正常细胞系中则不然。成纤维细胞和上皮细胞。此外，telomestatin 还诱导癌细胞系中后期桥的形成。端粒抑素的这些作用与显性失活 TRF2 的作用相似，TRF2 也会导致端粒 G 尾迅速丢失并诱导后期桥。这些结果表明，telomestatin不仅通过抑制端粒伸长发挥其抗癌作用，而且还通过快速破坏端粒末端的加帽功能来发挥其抗癌作用。与需要长期治疗的传统端粒酶抑制剂不同，G-四联体稳定剂telomestatin 可诱导细胞迅速死亡，并且选择性地对癌细胞有效。这项研究还确定了 TRF2 蛋白作为治疗多种癌症的治疗靶点，这些癌症在每条染色体的端粒 DNA 帽上都有 TRF2 蛋白。
Inhibition of telomerase activity by telomerase inhibitors induces a gradual loss of telomeres, and this in turn causes cancer cells to enter to a crisis stage. Here, we report the telomerase inhibitor telomestatin, which is known to stabilize G-quadruplex structures at 30 single-stranded telomeric overhangs ( G-tails), rapidly dissociates TRF2 from telomeres in cancer cells within a week, when given at a concentration that does not cause normal cells to die. The G-tails were dramatically reduced upon short-term treatment with the drug in cancer cell lines, but not in normal. broblasts and epithelial cells. In addition, telomestatin also induced anaphase bridge formation in cancer cell lines. These effects of telomestatin were similar to those of dominant negative TRF2, which also causes a prompt loss of the telomeric G-tails and induces an anaphase bridge. These results indicate that telomestatin exerts its anticancer effect not only through inhibiting telomere elongation, but also by rapidly disrupting the capping function at the very ends of telomeres. Unlike conventional telomerase inhibitors that require long-term treatments, the G-quadruplex stabilizer telomestatin induced prompt cell death, and it was selectively effective in cancer cells. This study also identifies the TRF2 protein as a therapeutic target for treating many types of cancer which have the TRF2 protein at caps of the telomere DNA of each chromosome.