温州医科大学刘志国课题组的一项最新研究，揭示了选择性TRF2抑制剂FKB04诱导肝癌细胞端粒缩短和衰老。2024年3月4日出版的《中国药理学报》发表了这项成果。

临床数据结合生物信息学分析表明TRF2在肝癌中过表达，并且高表达与预后不良相关。黄烷酮B衍生物FKB04在肝癌细胞中有效抑制了TRF2表达，而对其他五个端粒蛋白复合体的影响较小。此外，FKB04处理导致端粒缩短，并增加端粒自由端的数量，导致T环结构破坏。结果，FKB04促进了肝癌细胞衰老而不调节凋亡水平。

与这些发现一致的是，FKB04通过促进端粒TRF2缺陷诱导的端粒缩短，在小鼠移植瘤模型中抑制了肿瘤细胞的生长，且没有明显的副作用。这些结果表明TRF2是肝癌的潜在治疗靶点，并暗示FKB04可能是TRF2的选择性小分子抑制剂，在肝癌治疗中有前景。

据悉，端粒重复结合因子2（TRF2）是端粒蛋白复合体的关键组分，对维持基因组完整性至关重要。在多种恶性癌症中发现TRF2过表达，而其下调可能导致细胞死亡。尽管其潜在作用，但TRF2的选择性小分子抑制剂及其在肝癌治疗中的治疗效果，在很大程度上仍然未知。

附：英文原文

Title: Discovery of a selective TRF2 inhibitor FKB04 induced telomere shortening and senescence in liver cancer cells

Author: Qiu, Yin-da, Yan, Qi, Wang, Yi, Ye, Yan-fei, Wang, Yan, Wang, Meng-ying, Wang, Pei-pei, Zhang, Shu-yuan, Wang, Da-long, Yan, Hao, Ruan, Jing, Zhao, Yun-jie, Huang, Le-hao, Cho, Namki, Wang, Kun, Zheng, Xiao-hui, Liu, Zhi-guo

Issue&Volume: 2024-03-04

Abstract: Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.

DOI: 10.1038/s41401-024-01243-6

Source: https://www.nature.com/articles/s41401-024-01243-6