| 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 |
Related Documents
:
|
23349558 - The role of high mobility group box 1 chromosomal protein in the pathogenesis of chroni... 18508568 - Epcam-targeted induction of apoptosis. 19033458 - Microrna-184 antagonizes microrna-205 to maintain ship2 levels in epithelia. 15809718 - Expression of tnf-related apoptosis-inducing ligand in human hepatocellular carcinoma. 7433328 - Sarcoidosis associated with combined immunodeficiency. 22105648 - Cellular and molecular mechanisms of autoimmune disease. |
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: 2012-05-17 |
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 |
Affiliation:
|
Miles and Shirley Fiterman Center for Digestive Diseases, Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| 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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Extracellular and Intracellular Pattern Recognition Receptors Cooperate in the Recognition of Helico...
Next Document: A cost-utility analysis of ablative therapy for Barrett's esophagus.