Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
Combined treatment with emodin and a telomerase inhibitor induces significant telomere damage/dysfunction and cell death
复制标题
大黄素和端粒酶抑制剂联合治疗可诱导显着的端粒损伤/功能障碍和细胞死亡
DOI：
10.1038/s41419-019-1768-x
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发表时间：
2019-07-11
影响因子：
9
通讯作者：
Wang, Feng
中科院分区：
文献类型：
--
作者：
Liu, Rui;Liu, Jing;Wang, Feng
G-四链体端粒的二级结构代表自然的复制叉障碍，必须解决，以允许有效的复制。端粒G4的稳定导致端粒功能障碍，表现为端粒缩短或损伤，导致基因组不稳定和细胞凋亡。已经报道了靶向G4结构的化合物诱导端粒干扰和肿瘤抑制。在这里，使用PyRx在天然化合物库中进行虚拟筛选以鉴定新的G4配体。大黄素被确定为最佳候选物之一，显示出很大的G4结合潜力。随后，我们证实了大黄素可以在体外稳定G4结构，并触发端粒功能障碍，包括脆性端粒，端粒丢失和端粒DNA损伤。然而，这种端粒紊乱可以通过随后的端粒酶活性升高来挽救;相反，当我们在大黄素处理后用端粒酶抑制剂BIBR 1532处理细胞时，在小鼠中观察到永久性端粒紊乱和4 T1细胞异种移植肿瘤的明显生长抑制。总之，我们的研究结果首次表明，大黄素诱导的端粒DNA损伤可以上调端粒酶活性，这可能会削弱其抗癌作用。大黄素和端粒酶抑制剂的联合使用协同诱导端粒功能障碍，抑制肿瘤的产生。
G-quadruplex telomeric secondary structures represent natural replication fork barriers and must be resolved to permit efficient replication. Stabilization of telomeric G4 leads to telomere dysfunctions demonstrated by telomere shortening or damage, resulting in genome instability and apoptosis. Chemical compounds targeting G4 structures have been reported to induce telomere disturbance and tumor suppression. Here, virtual screening was performed in a natural compound library using PyRx to identify novel G4 ligands. Emodin was identified as one of the best candidates, showing a great G4-binding potential. Subsequently, we confirmed that emodin could stabilize G4 structures in vitro and trigger telomere dysfunctions including fragile telomeres, telomere loss, and telomeric DNA damage. However, this telomere disturbance could be rescued by subsequent elevation of telomerase activity; in contrast, when we treated the cells with the telomerase inhibitor BIBR1532 upon emodin treatment, permanent telomere disturbance and obvious growth inhibition of 4T1-cell xenograft tumors were observed in mice. Taken together, our results show for the first time that emodin-induced telomeric DNA damage can upregulate telomerase activity, which may weaken its anticancer effect. The combined use of emodin and the telomerase inhibitor synergistically induced telomere dysfunction and inhibited tumor generation.