Hu Po, Li Hui, Sun Wenzhuo, Wang Hongzheng, Yu Xiaoxuan, Qing Yingjie, Wang Zhanyu, Zhu Mengyuan, Xu Jingyan, Guo Qinglong, Hui Hui
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China.
Department of Pharmacology, School of Medicine & Holostic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, China.
Acta Pharm Sin B. 2021 Oct;11(10):3178-3192. doi: 10.1016/j.apsb.2021.02.004. Epub 2021 Feb 11.
The integrity of lysosomes is of vital importance to survival of tumor cells. We demonstrated that LW-218, a synthetic flavonoid, induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy. LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D, as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents, which can alter the activity of cathepsins. Lysophagy, was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB. LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator. Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy. LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1. Moreover, LW-218 inhibited the leukemia cell growth . Thus, the necessary impact of integral lysosomal function in cell rescue and death were illustrated.
溶酶体的完整性对于肿瘤细胞的存活至关重要。我们证明，合成类黄酮LW-218在血液系统恶性肿瘤中可诱导溶酶体迅速增大，并伴有溶酶体膜通透性增加。LW-218诱导的溶酶体损伤和溶酶体依赖性细胞死亡由组织蛋白酶D介导，因为溶酶体损伤和细胞凋亡可通过耗尽组织蛋白酶D或溶酶体碱化剂来抑制，这些试剂可改变组织蛋白酶的活性。自噬性溶酶体降解在LW-218处理后启动，用于细胞自我拯救，并与转录因子EB的钙释放和细胞核转位相关。LW-218处理增强了自噬相关基因的表达，而细胞内钙螯合剂可抑制这种表达。持续暴露于LW-218会耗尽溶酶体容量，从而抑制正常的自噬。LW-218与NPC细胞内胆固醇转运蛋白1相互作用导致溶酶体膜上胆固醇异常沉积，从而引发LW-218诱导的溶酶体增大和损伤。此外，LW-218抑制白血病细胞生长。因此，阐明了完整溶酶体功能在细胞拯救和死亡中的必要作用。
