Document Detail


Targeting glutamine metabolism sensitizes melanoma cells to TRAIL-induced death.
MedLine Citation:
PMID:  20599741     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Targeting specific metabolic pathways has emerged for cancer therapeutics. For melanoma, metabolic studies have solely focused on high glucose uptake. By contrast, little is known regarding addiction to glutamine. Using five melanoma lines and two normal cell types, addition of aminooxyacetate (AOA), an inhibitor of glutamate-dependent transaminase regulating glutaminolytic pathway, two lines underwent low levels of apoptosis (>30%), while the other three lines were resistant, as were normal cells to AOA. However, three resistant lines (but not normal cells), became sensitized to undergoing apoptosis when TRAIL was combined with AOA. TRAIL by itself had minimal effects on all cell lines and normal cells, and did not augment AOA-induced killing in the two sensitive melanoma lines. AOA plus TRAIL induced a caspase-dependent apoptotic response. AOA did not influence TRAIL DR4 or DR5 cell surface death receptor levels, but AOA enhanced pro-apoptotic protein levels of Noxa, while reducing pro-survival protein Mcl-1. To verify AOA was targeting glutamine pathway, depletion of glutamine produced similar results, because absence of glutamine sensitized three melanoma lines, but not fibroblasts to killing by TRAIL. Glutamine depletion also led to Noxa induction. These results indicate some lines are addicted to glutamine, and treatment with AOA or glutamine depletion sensitizes melanoma to TRAIL-mediated killing, while sparing normal cells. Future studies are indicated to translate these discoveries to metastatic melanoma as there is currently no treatment available to prolong survival.
Authors:
J-Z Qin; H Xin; B J Nickoloff
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-19
Journal Detail:
Title:  Biochemical and biophysical research communications     Volume:  398     ISSN:  1090-2104     ISO Abbreviation:  Biochem. Biophys. Res. Commun.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-19     Completed Date:  2010-08-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372516     Medline TA:  Biochem Biophys Res Commun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  146-52     Citation Subset:  IM    
Copyright Information:
Copyright 2010 Elsevier Inc. All rights reserved.
Affiliation:
Department of Pathology, Loyola University Medical Center, Maywood, IL 60153, USA.
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MeSH Terms
Descriptor/Qualifier:
Aminooxyacetic Acid / pharmacology
Apoptosis*
Cell Line, Tumor
Drug Resistance, Neoplasm*
Enzyme Inhibitors / pharmacology
Fibroblasts / drug effects
Glutamine / antagonists & inhibitors,  metabolism*
Humans
Melanocytes / drug effects
Melanoma / metabolism*
Receptors, Death Domain / metabolism
Skin Neoplasms / metabolism*
TNF-Related Apoptosis-Inducing Ligand / pharmacology*
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Receptors, Death Domain; 0/TNF-Related Apoptosis-Inducing Ligand; 56-85-9/Glutamine; 645-88-5/Aminooxyacetic Acid

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


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