Document Detail


Death receptor 5 internalization is required for lysosomal permeabilization by TRAIL in malignant liver cell lines.
MedLine Citation:
PMID:  19272388     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity in hepatocellular carcinoma cells is mediated by lysosomal permeabilization. Our aims were to determine which TRAIL receptor, death receptor (DR) 4 or DR5, mediates lysosomal permeabilization and assess whether receptor endocytosis followed by trafficking to lysosomes contributes in this process.
METHODS: TRAIL ligand internalization in Huh-7 cells was examined by confocal microscopy using Flag-tagged TRAIL, whereas DR4- and DR5-enhanced green fluorescent protein internalization was assessed by total internal reflection microscopy. Clathrin-dependent endocytosis was inhibited by expressing dominant negative dynamin.
RESULTS: Although Huh-7 cells express both TRAIL receptors, short hairpin RNA silencing of DR5 but not DR4 attenuated TRAIL-mediated lysosomal permeabilization and apoptosis. The TRAIL/DR5 complex underwent rapid cellular internalization upon ligand stimulation, whereas the TRAIL/DR4 complex was not efficiently internalized. DR5-enhanced green fluorescent protein internalization was dependent on a dileucine-based internalization motif. Endocytosis of the TRAIL/DR5 complex was dynamin dependent and was required for rapid lysosomal permeabilization and apoptosis in multiple malignant hepatocellular and cholangiocarcinoma cell lines. Upon TRAIL treatment, DR5 colocalized with lysosomes after internalization. Inhibition of DR5 trafficking to lysosomes by Rab7 small interfering RNA also reduced TRAIL-mediated lysosomal disruption and apoptosis.
CONCLUSIONS: TRAIL-mediated endocytosis of DR5 with trafficking to lysosomes contributes to lysosomal protease release into the cytosol and efficient apoptosis in malignant liver cell lines.
Authors:
Yuko Akazawa; Justin L Mott; Steven F Bronk; Nathan W Werneburg; Alisan Kahraman; Maria Eugenia Guicciardi; Xue Wei Meng; Shigeru Kohno; Vijay H Shah; Scott H Kaufmann; Mark A McNiven; Gregory J Gores
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-03-09
Journal Detail:
Title:  Gastroenterology     Volume:  136     ISSN:  1528-0012     ISO Abbreviation:  Gastroenterology     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-06-08     Completed Date:  2009-07-08     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  0374630     Medline TA:  Gastroenterology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2365-2376.e1-7     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / genetics,  physiology*
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Humans
Liver Neoplasms / pathology
Lysosomes / genetics,  metabolism*
Microscopy, Confocal
Probability
RNA Interference / physiology
Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics,  metabolism*
Receptors, Tumor Necrosis Factor / genetics,  metabolism*
Sensitivity and Specificity
Grant Support
ID/Acronym/Agency:
CA69008/CA/NCI NIH HHS; DK 44650/DK/NIDDK NIH HHS; DK 9875/DK/NIDDK NIH HHS; DK63947/DK/NIDDK NIH HHS; HL86990/HL/NHLBI NIH HHS; R01 DK059615/DK/NIDDK NIH HHS; R01 DK063947-06/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Receptors, TNF-Related Apoptosis-Inducing Ligand; 0/Receptors, Tumor Necrosis Factor; 0/TNFRSF10A protein, human
Comments/Corrections

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