Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy:Dynamic analysis on cytotoxic effects of LW-218

• 作者: Po Hu Hui Li Wenzhuo Sun Hongzheng Wang Xiaoxuan Yu Yingjie Qing Zhanyu Wang Mengyuan Zhu Jingyan Xu Qinglong Guo Hui Hui
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（10）
• 所属期刊栏目: Original articles
• 页码范围: 3178-3192
• 页数: 15页
• 语种: 英文

摘要

The integrity of lysosomes is of vital importance to survival of tumor ceils.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 choles-terol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracel-lular cholesterol transporter 1.Moreover,LW-218 inhibited the leukemia cell growth in vivo.Thus,the necessary impact of integral lysosomal function in cell rescue and death were illustrated.