Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218
| العنوان: | Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218 |
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| المؤلفون: | Po Hu, Hongzheng Wang, Xiaoxuan Yu, Wenzhuo Sun, Hui Hui, Hui Li, Mengyuan Zhu, Zhanyu Wang, Jingyan Xu, Qinglong Guo, Yingjie Qing |
| المصدر: | Acta Pharmaceutica Sinica B, Vol 11, Iss 10, Pp 3178-3192 (2021) Acta Pharmaceutica Sinica. B |
| بيانات النشر: | Elsevier, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | NPC, Niemann-Pick type disease C, Cathepsin D, ATG, autophagy related, NH4Cl, ammonium chloride, Lysosomal damage, Calcium in biology, Hematological malignancies, 0302 clinical medicine, RAB7A, RAS-related protein RAB-7a, K48, lysine 48, LC3, microtubule-associated protein 1 light chain 3, TFEB, transcription factor EB, General Pharmacology, Toxicology and Pharmaceutics, 0303 health sciences, RT-qPCR, real time quantitative PCR, Chemistry, LCD, lysosome-dependent cell death, CaN, calcineurin, P62/SQSTM1, sequestosome 1, Cell biology, TRPML1, transient receptor potential mucolipin 1, medicine.anatomical_structure, Cholesterol, 030220 oncology & carcinogenesis, shRNA, short hairpin RNA, Original Article, CsA, cyclosporine A, DAPI, 4′,6-diamidino-2-phenylindole dihydrochloride, Programmed cell death, AO, acridine orange, CTSD, cathepsin D, LW-218, PBS, phosphate-buffered saline, CTSB, cathepsin B, LMP, lysosome membrane permeabilization, EGTA, ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid, RM1-950, Lysosome-dependent cell death, 03 medical and health sciences, Dex, dexamethasone, ROS, reactive oxygen species, FBS, fetal bovine serum, Lysosome, NPC1, NPC intracellular cholesterol transporter 1, medicine, BAF A1, bafilomycin A1, 030304 developmental biology, Cathepsin, PBMCs, peripheral blood mononuclear cells, Lysosomal membrane permeabilization, K63, lysine 63, Cell growth, DCFH-DA, 2,7-dichlorodi-hydrofluorescein diacetate, Autophagy, BID, BH3-interacting domain death agonist, Lysophagy, OD, optical density, TFEB, CCK8, Cell Counting Kit, Therapeutics. Pharmacology, LAMPs, lysosomal-associated membrane proteins |
| الوصف: | 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. Graphical abstract 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.Image 1 |
| اللغة: | English |
| تدمد: | 2211-3835 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bc2bc1bb062d92dcf545995a174a1320 http://www.sciencedirect.com/science/article/pii/S2211383521000411 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....bc2bc1bb062d92dcf545995a174a1320 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22113835 |
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