Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218 |
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| Authors: | Po Hu Hui Li Wenzhuo Sun Hongzheng Wang Xiaoxuan Yu Yingjie Qing Zhanyu Wang Mengyuan Zhu Jingyan Xu Qinglong Guo Hui Hui |
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| Affiliation: | 1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China;2. Department of Pharmacology, School of Medicine & Holostic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210046, China;3. Department of Hematology, the Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing 210008, China |
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| Abstract: | 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. |
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| Keywords: | LW-218 Lysosomal damage Lysophagy Lysosomal membrane permeabilization Lysosome-dependent cell death Cholesterol Cathepsin D Hematological malignancies AO},{#name:keyword,$:{id:kwrd0055},$$:[{#name:text,_:acridine orange ATG},{#name:keyword,$:{id:kwrd0065},$$:[{#name:text,_:autophagy related BAF A1},{#name:keyword,$:{id:kwrd0075},$$:[{#name:text,_:bafilomycin A1 BID},{#name:keyword,$:{id:kwrd0085},$$:[{#name:text,_:BH3-interacting domain death agonist CaN},{#name:keyword,$:{id:kwrd0095},$$:[{#name:text,_:calcineurin CCK8},{#name:keyword,$:{id:kwrd0105},$$:[{#name:text,_:Cell Counting Kit CsA},{#name:keyword,$:{id:kwrd0115},$$:[{#name:text,_:cyclosporine A CTSB},{#name:keyword,$:{id:kwrd0125},$$:[{#name:text,_:cathepsin B CTSD},{#name:keyword,$:{id:kwrd0135},$$:[{#name:text,_:cathepsin D DAPI},{#name:keyword,$:{id:kwrd0145},$$:[{#name:text,_:4′,6-diamidino-2-phenylindole dihydrochloride DCFH-DA},{#name:keyword,$:{id:kwrd0155},$$:[{#name:text,_:2,7-dichlorodi-hydrofluorescein diacetate Dex},{#name:keyword,$:{id:kwrd0165},$$:[{#name:text,_:dexamethasone EGTA},{#name:keyword,$:{id:kwrd0175},$$:[{#name:text,$$:[{#name:__text__,_:ethylene glycol-bis(2-aminoethyl ether)-},{#name:italic,_:N},{#name:__text__,_:,},{#name:italic,_:N},{#name:__text__,_:,},{#name:italic,_:N},{#name:__text__,_:′,},{#name:italic,_:N},{#name:__text__,_:′-tetraacetic acid FBS},{#name:keyword,$:{id:kwrd0185},$$:[{#name:text,_:fetal bovine serum K48},{#name:keyword,$:{id:kwrd0195},$$:[{#name:text,_:lysine 48 K63},{#name:keyword,$:{id:kwrd0205},$$:[{#name:text,_:lysine 63 LAMPs},{#name:keyword,$:{id:kwrd0215},$$:[{#name:text,_:lysosomal-associated membrane proteins LC3},{#name:keyword,$:{id:kwrd0225},$$:[{#name:text,_:microtubule-associated protein 1 light chain 3 LCD},{#name:keyword,$:{id:kwrd0235},$$:[{#name:text,_:lysosome-dependent cell death LMP},{#name:keyword,$:{id:kwrd0245},$$:[{#name:text,_:lysosome membrane permeabilization ammonium chloride NPC},{#name:keyword,$:{id:kwrd0265},$$:[{#name:text,_:Niemann-Pick type disease C NPC1},{#name:keyword,$:{id:kwrd0275},$$:[{#name:text,_:NPC intracellular cholesterol transporter 1 OD},{#name:keyword,$:{id:kwrd0285},$$:[{#name:text,_:optical density P62/SQSTM1},{#name:keyword,$:{id:kwrd0295},$$:[{#name:text,_:sequestosome 1 PBMCs},{#name:keyword,$:{id:kwrd0305},$$:[{#name:text,_:peripheral blood mononuclear cells PBS},{#name:keyword,$:{id:kwrd0315},$$:[{#name:text,_:phosphate-buffered saline RAB7A},{#name:keyword,$:{id:kwrd0325},$$:[{#name:text,_:RAS-related protein RAB-7a ROS},{#name:keyword,$:{id:kwrd0335},$$:[{#name:text,_:reactive oxygen species RT-qPCR},{#name:keyword,$:{id:kwrd0345},$$:[{#name:text,_:real time quantitative PCR shRNA},{#name:keyword,$:{id:kwrd0355},$$:[{#name:text,_:short hairpin RNA TFEB},{#name:keyword,$:{id:kwrd0365},$$:[{#name:text,_:transcription factor EB TRPML1},{#name:keyword,$:{id:kwrd0375},$$:[{#name:text,_:transient receptor potential mucolipin 1 |
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