Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect
Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect
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DOI：
10.1172/jci32461
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发表时间：
2007-11-01
影响因子：
15.9
通讯作者：
Biroccio, Annamaria
中科院分区：
文献类型：
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作者：
Salvati, Erica;Leonetti, Carlo;Biroccio, Annamaria
端粒的功能是癌细胞复制所必需的。富含G的端粒DNA链可以折叠成被称为G-四链(G4)的四链结构，其稳定性改变了端粒的功能，限制了癌细胞的生长。因此，G4配体RHPS4可能具有抗肿瘤活性。在这里，我们证明了RHPS4在人转化的成纤维细胞和黑色素瘤细胞中触发了快速而有效的DNA损伤反应，其特征是形成了几个包含磷酸化DNA损伤反应因子伽马-H_2AX、RAD17和53BP1的端粒灶。这依赖于DNA修复酶ATR，与保护性端粒DNA结合蛋白POT1的去定位相关，并被POT1或TRF2的过度表达所拮抗。在小鼠体内，RHPS4通过端粒损伤和肿瘤细胞凋亡对不同组织类型的人肿瘤细胞移植瘤起到抗肿瘤作用。肿瘤抑制伴随着强烈的DNA损伤反应，过表达POT1或TRF2的肿瘤对RHPS4治疗耐药。这些数据提供了RHPS4是端粒损伤诱导剂的证据，并且在肿瘤细胞中选择性地触发端粒破坏导致了小鼠的高治疗指数。他们还定义了端粒损伤和抗肿瘤活性之间的功能联系，并揭示了端粒保护因子TRF2和POT1在这一抗端粒策略中的关键作用。
Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors gamma-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.