Research Institute for Microbial Diseases (RIMD), Osaka University, Suita, 565-0871, Japan.
Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
Nat Commun. 2020 Apr 22;11(1):1935. doi: 10.1038/s41467-020-15719-6.
Although cellular senescence acts primarily as a tumour suppression mechanism, the accumulation of senescent cells in vivo eventually exerts deleterious side effects through inflammatory/tumour-promoting factor secretion. Thus, the development of new drugs that cause the specific elimination of senescent cells, termed senolysis, is anticipated. Here, by an unbiased high-throughput screening of chemical compounds and a bio-functional analysis, we identify BET family protein degrader (BETd) as a promising senolytic drug. BETd provokes senolysis through two independent but integrated pathways; the attenuation of non-homologous end joining (NHEJ), and the up-regulation of autophagic gene expression. BETd treatment eliminates senescent hepatic stellate cells in obese mouse livers, accompanied by the reduction of liver cancer development. Furthermore, the elimination of chemotherapy-induced senescent cells by BETd increases the efficacy of chemotherapy against xenograft tumours in immunocompromised mice. These results reveal the vulnerability of senescent cells and open up possibilities for its control.
虽然细胞衰老主要作为一种肿瘤抑制机制起作用，但衰老细胞在体内的积累最终通过炎症/肿瘤促进因子的分泌产生有害的副作用。因此，人们期望开发出一种新的药物，能够特异性地消除衰老细胞，称为衰老细胞溶解。在这里，我们通过对化学化合物的无偏见高通量筛选和生物功能分析，鉴定出 BET 家族蛋白降解剂（BETd）是一种有前途的衰老细胞溶解药物。BETd 通过两种独立但整合的途径诱导衰老细胞溶解；非同源末端连接（NHEJ）的衰减和自噬基因表达的上调。BETd 处理消除了肥胖小鼠肝脏中的衰老肝星状细胞，伴随着肝癌发展的减少。此外，BETd 消除化疗诱导的衰老细胞增加了化疗对免疫缺陷小鼠异种移植肿瘤的疗效。这些结果揭示了衰老细胞的脆弱性，并为其控制提供了可能性。
