Targeting the lysosome by an aminomethylated Riccardin D triggers DNA damage through cathepsin B-mediated degradation of BRCA1
Targeting the lysosome by an aminomethylated Riccardin D triggers DNA damage through cathepsin B-mediated degradation of BRCA1
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氨甲基化 Riccardin D 靶向溶酶体，通过组织蛋白酶 B 介导的 BRCA1 降解触发 DNA 损伤
DOI：
10.1111/jcmm.14077
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发表时间：
2019
影响因子：
5.3
通讯作者：
Lou Hongxiang
中科院分区：
文献类型：
--
作者：
Wang Yanyan;Niu Huanmin;Hu Zhongyi;Zhu Mengyuan;Wang Lining;Han Lili;Qian Lilin;Tian Keli;Yuan Huiqing;Lou Hongxiang
RD‐N是一种里卡多菌素D的氨甲基化衍生物，是一种促溶酶体剂，可触发前列腺癌（PCa）细胞中溶酶体膜透化，随后发生组织蛋白酶B（CTSB）依赖性凋亡，但其潜在机制仍不清楚。在这里，我们表明RD-N治疗驱动CTSB从溶酶体易位到细胞核，在那里它通过抑制乳腺癌1蛋白（BRCA 1）促进DNA损伤。CTSB活性的抑制剂，或CTSB靶向siRNA或CTSB与酶阴性结构域减弱BRCA 1的激活和RD-N诱导的DNA损伤。相反，CTSB过表达导致BRCA 1抑制，并使PCa细胞对RD-N-诱导的细胞死亡敏感。此外，在BRCA 1缺陷型癌细胞中，RD-N-诱导的细胞死亡加剧。我们还证明了CTSB/BRCA 1依赖性DNA损伤对RD-N至关重要，但对依托泊苷无关，这加强了CTSB/BRCA 1在RD-N介导的细胞死亡中的重要性。此外，RD‐N协同增加细胞对顺铂的敏感性，这种作用在BRCA 1缺陷癌细胞中更为明显。这项研究揭示了一种新的分子机制，即RD‐N通过抑制PCa细胞中的BRCA 1促进CTSB依赖性DNA损伤，从而鉴定出一种靶向溶酶体用于癌症治疗的潜在化合物。
RD‐N, an aminomethylated derivative of riccardin D, is a lysosomotropic agent that can trigger lysosomal membrane permeabilization followed by cathepsin B (CTSB)‐dependent apoptosis in prostate cancer (PCa) cells, but the underlying mechanisms remain unknown. Here we show that RD‐N treatment drives CTSB translocation from the lysosomes to the nucleus where it promotes DNA damage by suppression of the breast cancer 1 protein (BRCA1). Inhibition of CTSB activity with its specific inhibitors, or by CTSB‐targeting siRNA or CTSB with enzyme‐negative domain attenuated activation of BRCA1 and DNA damage induced by RD‐N. Conversely, CTSB overexpression resulted in inhibition of BRCA1 and sensitized PCa cells to RD‐N‐induced cell death. Furthermore, RD‐N‐induced cell death was exacerbated in BRCA1‐deficient cancer cells. We also demonstrated that CTSB/BRCA1‐dependent DNA damage was critical for RD‐N, but not for etoposide, reinforcing the importance of CTSB/BRCA1 in RD‐N‐mediated cell death. In addition, RD‐N synergistically increased cell sensitivity to cisplatin, and this effect was more evidenced in BRCA1‐deficient cancer cells. This study reveals a novel molecular mechanism that RD‐N promotes CTSB‐dependent DNA damage by the suppression of BRCA1 in PCa cells, leading to the identification of a potential compound that target lysosomes for cancer treatment.