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 i...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.展开更多
基金supported by the Nation Natural Science Foundation of China(81873046,81830105,81903647,81503096,and 81673461)the Drug Innovation Major Project(2017ZX09301014,2018ZX09711001-003-007,and 2017ZX09101003-005-023,China)+4 种基金Natural Science Foundation of Jiangsu province(BK20190560 and BE2018711,China)Nanjing Medical Science and Technology Development Project(YKK17074 and YKK19064,China)Research and Innovation Project for College Graduates of Jiangsu Province(KYCX180803,China)China Postdoctoral Science Foundation(No.2018M642373)“Double First-Class”University project(CPU 2018GF11 and CPU2018GF05,China)。
文摘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.
