Curcusone C induces telomeric DNA-damage response in cancer cells through inhibition of telomeric repeat factor 2
Curcusone C induces telomeric DNA-damage response in cancer cells through inhibition of telomeric repeat factor 2
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Curcusone C 通过抑制端粒重复因子 2 诱导癌细胞中的端粒 DNA 损伤反应
DOI：
10.1016/j.bbapap.2017.08.022
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发表时间：
2017-11-01
影响因子：
3.2
通讯作者：
Li, Ding
中科院分区：
文献类型：
--
作者：
Wang, Mingxue;Cao, Jiaojiao;Li, Ding
端粒重复因子2 （TRF2或TERF2）是端粒保护蛋白复合物Shelterin的关键成分。TRF2有助于端粒折叠形成t环结构，抑制ATM依赖性DNA损伤反应激活。TRF2已被公认为癌症治疗的潜在新靶点。在常规小分子文库筛选中，我们发现Curcusone C在破坏TRF2与端粒DNA结合方面有显著作用，对癌细胞具有较强的抗肿瘤活性。我们的研究结果表明，Curcusone C可以与TRF2结合而不与TRF1（端粒重复因子1）结合，尽管这两种蛋白具有很高的序列同源性，这表明它们在端粒中的结合构象和生物学功能可能不同。我们的机制研究表明，Curcusone C可能通过其DNA结合位点与TRF2结合，导致其与端粒DNA的相互作用受阻。进一步的细胞研究表明，TRF2与Curcusone C相互作用可激活dna损伤反应，抑制肿瘤细胞增殖，引起细胞周期阻滞，导致肿瘤细胞凋亡。我们的研究表明，Curcusone C可能成为一种有前途的先导化合物，用于进一步开发癌症治疗。本文首次发现TRF2是Curcusone c的靶点，其他一些萜类化合物的抗癌活性可能与其对端粒保护蛋白的可能作用有关。
Telomeric repeat factor 2 (known as TRF2 or TERF2) is a key component of telomere protection protein complex named as Shelterin. TRF2 helps the folding of telomere to form T-loop structure and the suppression of ATM dependent DNA damage response activation. TRF2 has been recognized as a potentially new therapeutic target for cancer treatment. In our routine screening of small molecule libraries, we found that Curcusone C had significant effect in disrupting the binding between TRF2 and telomeric DNA, with potent antitumor activity against cancer cells. Our result showed that Curcusone C could bind with TRF2 without binding interaction with TRF1 (telomeric repeat factor 1) although these two proteins share high sequence homology, indicating that their binding conformations and biological functions in telomere could be different. Our mechanistic studies showed that Curcusone C bound with TRF2 possibly through its DNA binding site causing blockage of its interaction with telomeric DNA. Further in cellular studies indicated that the interaction of TRF2 with Curcusone C could activate DNA-damage response, inhibit tumor cell proliferation, and cause cell cycle arrest, resulting in tumor cell apoptosis. Our studies showed that Curcusone C could become a promising lead compound for further development for cancer treatment. Here, TRF2 was firstly identified as a target of Curcusone C. It is likely that the anti -cancer activity of some other terpenes and terpenoids are related with their possible effect for telomere protection proteins.