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

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-depende...

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Published in:Acta pharmaceutica Sinica. B 2021-10, Vol.11 (10), p.3178-3192
Main Authors: Hu, Po, Li, Hui, Sun, Wenzhuo, Wang, Hongzheng, Yu, Xiaoxuan, Qing, Yingjie, Wang, Zhanyu, Zhu, Mengyuan, Xu, Jingyan, Guo, Qinglong, Hui, Hui
Format: Article
Language:English
Subjects:
Cathepsin D
Cholesterol
Hematological malignancies
LW-218
Lysophagy
Lysosomal damage
Lysosomal membrane permeabilization
Lysosome-dependent cell death
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Summary: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 in vivo. Thus, the necessary impact of integral lysosomal function in cell rescue and death were illustrated. LW-218-induced cholesterol accumulation on lysosomes via NPC1 binding can elicit lysosomal damage followed by lysophagy and lysosome-dependent cell death in hematological malignancies cells. [Display omitted]
ISSN:2211-3835
2211-3843
DOI:10.1016/j.apsb.2021.02.004