Document Detail


Proteasomal regulation of caspase-8 in cancer cell apoptosis.
MedLine Citation:
PMID:  23456622     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Previous studies demonstrated that proteasome inhibition sensitizes TRAIL resistant prostate cancer cells to TRAIL-mediated apoptosis via stabilization of the active p18 subunit of caspase-8. The present study investigated the impact of proteasome inhibition on caspase-8 stability, ubiquitination, trafficking, and activation in cancer cells. Using caspase-8 deficient neuroblastoma (NB7) cells for reconstituting non-cleavable mutant forms of caspase-8, we demonstrated that the non-cleavable forms of caspase-8 are capable of inducing apoptosis comparably to wild-type caspase-8, in response to proteasome inhibitor and GST-TRAIL. Moreover in the LNCaP human prostate cancer cells, caspase-8 polyubiquitination occurs after TRAIL stimulation and caspase-8 processing. Subcellular fractionation analysis revealed caspase-8 activity in both cytosol and plasma membrane fractions in both NB7 reconstituted caspase-8 cell lines, as well the LNCaP prostate cancer cells. The present results suggest that caspase-8 stabilization through proteasome inhibition leads to reactivation of the extrinsic pathway of apoptosis and identify E3 ligase mediating caspase-8 polyubiquitination, as a novel molecular target. Inhibition of this E3 ligase in combination with TRAIL towards restoring apoptosis signaling activation may have potential therapeutic significance in resistant tumors.
Authors:
Michael V Fiandalo; Steven R Schwarze; Natasha Kyprianou
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Apoptosis : an international journal on programmed cell death     Volume:  18     ISSN:  1573-675X     ISO Abbreviation:  Apoptosis     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-04-25     Completed Date:  2013-11-26     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  9712129     Medline TA:  Apoptosis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  766-76     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects*
Caspase 8 / genetics,  metabolism*
Cell Line, Tumor
Enzyme Activation
Humans
Male
Prostatic Neoplasms / drug therapy
Proteasome Endopeptidase Complex / drug effects,  metabolism*
TNF-Related Apoptosis-Inducing Ligand / metabolism,  pharmacology
Ubiquitination
Grant Support
ID/Acronym/Agency:
R01 DK083761/DK/NIDDK NIH HHS; R01 DK083761/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; EC 3.4.22.-/Caspase 8; EC 3.4.25.1/Proteasome Endopeptidase Complex
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Secondary mutations of c-KIT contribute to acquired resistance to imatinib and decrease efficacy of ...
Next Document:  The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal ca...