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

التفاصيل البيبلوغرافية
العنوان: Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218.
المؤلفون: Hu P; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China., Li H; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China., Sun W; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China., Wang H; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China., Yu X; 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., Qing Y; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China., Wang Z; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China., Zhu M; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China., Xu J; Department of Hematology, the Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing 210008, China., Guo Q; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China., Hui H; State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China.
المصدر: Acta pharmaceutica Sinica. B [Acta Pharm Sin B] 2021 Oct; Vol. 11 (10), pp. 3178-3192. Date of Electronic Publication: 2021 Feb 11.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101600560 Publication Model: Print-Electronic Cited Medium: Print ISSN: 2211-3835 (Print) Linking ISSN: 22113835 NLM ISO Abbreviation: Acta Pharm Sin B Subsets: PubMed not MEDLINE
أسماء مطبوعة: Original Publication: [Amsterdam] : Elsevier, 2011-
مستخلص: 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.
(© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)
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فهرسة مساهمة: Keywords: AO, acridine orange; ATG, autophagy related; BAF A1, bafilomycin A1; BID, BH3-interacting domain death agonist; CCK8, Cell Counting Kit; CTSB, cathepsin B; CTSD, cathepsin D; CaN, calcineurin; Cathepsin D; Cholesterol; CsA, cyclosporine A; DAPI, 4′,6-diamidino-2-phenylindole dihydrochloride; DCFH-DA, 2,7-dichlorodi-hydrofluorescein diacetate; Dex, dexamethasone; EGTA, ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid; FBS, fetal bovine serum; Hematological malignancies; K48, lysine 48; K63, lysine 63; LAMPs, lysosomal-associated membrane proteins; LC3, microtubule-associated protein 1 light chain 3; LCD, lysosome-dependent cell death; LMP, lysosome membrane permeabilization; LW-218; Lysophagy; Lysosomal damage; Lysosomal membrane permeabilization; Lysosome-dependent cell death; NH4Cl, ammonium chloride; NPC, Niemann-Pick type disease C; NPC1, NPC intracellular cholesterol transporter 1; OD, optical density; P62/SQSTM1, sequestosome 1; PBMCs, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; RAB7A, RAS-related protein RAB-7a; ROS, reactive oxygen species; RT-qPCR, real time quantitative PCR; TFEB, transcription factor EB; TRPML1, transient receptor potential mucolipin 1; shRNA, short hairpin RNA
تواريخ الأحداث: Date Created: 20211103 Latest Revision: 20240817
رمز التحديث: 20240817
مُعرف محوري في PubMed: PMC8546890
DOI: 10.1016/j.apsb.2021.02.004
PMID: 34729308
قاعدة البيانات: MEDLINE
الوصف
تدمد:2211-3835
DOI:10.1016/j.apsb.2021.02.004