内吞作用
内体
细胞生物学
细胞内
自噬
癌细胞
程序性细胞死亡
生物
蛋白激酶B
受体酪氨酸激酶
细胞
化学
信号转导
细胞凋亡
生物化学
癌症
遗传学
作者
Omer F. Kuzu,Raghavendra Gowda,Arti Sharma,Gavin P. Robertson
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2014-07-01
卷期号:13 (7): 1690-1703
被引量:64
标识
DOI:10.1158/1535-7163.mct-13-0868
摘要
Abstract Leelamine is a promising compound for the treatment of cancer; however, the molecular mechanisms leading to leelamine-mediated cell death have not been identified. This report shows that leelamine is a weakly basic amine with lysosomotropic properties, leading to its accumulation inside acidic organelles such as lysosomes. This accumulation leads to homeostatic imbalance in the lysosomal endosomal cell compartments that disrupts autophagic flux and intracellular cholesterol trafficking as well as receptor-mediated endocytosis. Electron micrographs of leelamine-treated cancer cells displayed accumulation of autophagosomes, membrane whorls, and lipofuscin-like structures, indicating disruption of lysosomal cell compartments. Early in the process, leelamine-mediated killing was a caspase-independent event triggered by cholesterol accumulation, as depletion of cholesterol using β-cyclodextrin treatment attenuated the cell death and restored the subcellular structures identified by electron microscopy. Protein microarray–based analyses of the intracellular signaling cascades showed alterations in RTK–AKT/STAT/MAPK signaling cascades, which was subsequently confirmed by Western blotting. Inhibition of Akt, Erk, and Stat signaling, together with abnormal deregulation of receptor tyrosine kinases, was caused by the inhibition of receptor-mediated endocytosis. This study is the first report demonstrating that leelamine is a lysosomotropic, intracellular cholesterol transport inhibitor with potential chemotherapeutic properties leading to inhibition of autophagic flux and induction of cholesterol accumulation in lysosomal/endosomal cell compartments. Importantly, the findings of this study show the potential of leelamine to disrupt cholesterol homeostasis for treatment of advanced-stage cancers. Mol Cancer Ther; 13(7); 1690–703. ©2014 AACR.
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