TRF2 inhibition triggers apoptosis and reduces tumourigenicity of human melanoma cells
TRF2 inhibition triggers apoptosis and reduces tumourigenicity of human melanoma cells
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DOI：
10.1016/j.ejca.2006.03.010
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发表时间：
2006-08-01
影响因子：
8.4
通讯作者：
Gilson, Eric
中科院分区：
文献类型：
--
作者：
Biroccio, Annamaria;Rizzo, Angela;Gilson, Eric
端粒结合蛋白TRF2的抑制通过表达显性负型TRF2(Delta B Delta C)，已被用作抗端粒策略的模型，以诱导M14和JR5人黑色素瘤细胞系恶性表型的逆转。TRF2(Delta B Delta C)的过表达仅在JR5细胞中诱导细胞凋亡和降低致瘤性。P53和Rb的状态以及对DNA损伤的凋亡反应似乎不能解释这两种细胞对TRF2抑制的不同反应。有趣的是，与M14细胞相比，JR5细胞具有更短和更多功能失调的端粒。此外，G-四链相互作用剂(G4-配体)RHPS4处理使M14细胞对TRF2抑制敏感。这些结果表明，TRF2可以损害人类癌细胞的致瘤性。他们进一步表明，基础水平的端粒不稳定有利于对TRF2抑制的有效反应，联合抗TRF2和G4配体治疗将对肿瘤细胞生长具有协同抑制作用。
The inhibition of the telomere-binding protein TRF2, by expressing the dominant negative form TRF2(Delta B Delta C), has been used as a model of anti-telomere strategy to induce a reversion of the malignant phenotype of M14 and JR5 human melanoma lines. Over-expression of TRF2(Delta B Delta C) induced apoptosis and reduced tumourigenicity exclusively in JR5 cells. p53 and Rb status and apoptotic response to DNA damage did not seem to account for the different response of the two lines to TRF2 inhibition. Interestingly, JR5 cells possess shorter and more dysfunctional telomeres compared to M14 line. Moreover, the treatment with the G-quadruplex-interacting agent (G4-ligand) RHPS4 sensitises M14 cells to TRF2 inhibition. These results demonstrate that TRF2 can impair tumourigenicity of human cancer cells. They further suggest that a basal level of telomere instability favours an efficient response to TRF2 inhibition and that a combined anti-TRF2 and G4-ligand therapy would have synergistic inhibitory effects on tumour cell growth.