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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| Format: | Article |
| Language: | English |
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Elsevier
2021-10-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383521000411 |
| _version_ | 1818576192554401792 |
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| author | Po Hu Hui Li Wenzhuo Sun Hongzheng Wang Xiaoxuan Yu Yingjie Qing Zhanyu Wang Mengyuan Zhu Jingyan Xu Qinglong Guo Hui Hui |
| author_facet | Po Hu Hui Li Wenzhuo Sun Hongzheng Wang Xiaoxuan Yu Yingjie Qing Zhanyu Wang Mengyuan Zhu Jingyan Xu Qinglong Guo Hui Hui |
| author_sort | Po Hu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T06:10:07Z |
| format | Article |
| id | doaj.art-7db0874ddcbc4746ba8c5c3cbf5f5a61 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-12-16T06:10:07Z |
| publishDate | 2021-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-7db0874ddcbc4746ba8c5c3cbf5f5a612022-12-21T22:41:25ZengElsevierActa Pharmaceutica Sinica B2211-38352021-10-01111031783192Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218Po Hu0Hui Li1Wenzhuo Sun2Hongzheng Wang3Xiaoxuan Yu4Yingjie Qing5Zhanyu Wang6Mengyuan Zhu7Jingyan Xu8Qinglong Guo9Hui Hui10State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, ChinaState 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, ChinaState Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, ChinaState Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, ChinaDepartment of Hematology, the Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing 210008, ChinaState Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China; Corresponding authors. Tel./fax: +86 25 83271055.State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China; Corresponding authors. Tel./fax: +86 25 83271055.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.http://www.sciencedirect.com/science/article/pii/S2211383521000411LW-218Lysosomal damageLysophagyLysosomal membrane permeabilizationLysosome-dependent cell deathCholesterol |
| spellingShingle | Po Hu Hui Li Wenzhuo Sun Hongzheng Wang Xiaoxuan Yu Yingjie Qing Zhanyu Wang Mengyuan Zhu Jingyan Xu Qinglong Guo Hui Hui Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218 Acta Pharmaceutica Sinica B LW-218 Lysosomal damage Lysophagy Lysosomal membrane permeabilization Lysosome-dependent cell death Cholesterol |
| title | Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218 |
| title_full | Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218 |
| title_fullStr | Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218 |
| title_full_unstemmed | Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218 |
| title_short | Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218 |
| title_sort | cholesterol associated lysosomal disorder triggers cell death of hematological malignancy dynamic analysis on cytotoxic effects of lw 218 |
| topic | LW-218 Lysosomal damage Lysophagy Lysosomal membrane permeabilization Lysosome-dependent cell death Cholesterol |
| url | http://www.sciencedirect.com/science/article/pii/S2211383521000411 |
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