标题：Targeting the lysosome by an aminomethylated Riccardin D triggers DNA damage through cathepsin B-mediated degradation of BRCA1
作者：Wang, Yanyan; Niu, Huanmin; Hu, Zhongyi; Zhu, Mengyuan; Wang, Lining; Han, Lili; Qian, Lilin; Tian, Keli; Yuan, Huiqing; Lou, Hongxi 更多 作者机构：[Wang, Yanyan; Zhu, Mengyuan; Wang, Lining; Lou, Hongxiang] Shandong Univ, Sch Pharmaceut Sci, Dept Nat Prod Chem, Key Lab Chem Biol,Minist Educ, Jina 更多
通讯作者：Lou, HX;Yuan, HQ
通讯作者地址：[Lou, HX]Shandong Univ, Sch Pharmaceut Sci, Dept Nat Prod Chem, Key Lab Chem Biol,Minist Educ, Jinan, Shandong, Peoples R China;[Yuan, HQ]Shandong Uni 更多
来源：JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
关键词：BRCA1; CTSB; DNA damage; RD-N
摘要：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.