Document Detail


Differential genomic and proteomic profiling of glioblastoma cells exposed to terpyridineplatinum(II) complexes.
MedLine Citation:
PMID:  19439228     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Terpyridineplatinum(II) complexes (TPCs) efficiently inhibit the proliferation of glioblastoma cells in vitro and have been tested successfully in a rodent glioblastoma model. Apart from intercalation with DNA, the major mechanism of action of TPCs is a very potent and specific interaction with the human selenoprotein thioredoxin reductase (TrxR). TrxR plays a crucial role in cellular redox homeostasis and protection against oxidative damage. In many malignant cells the thioredoxin system is upregulated, promoting tumor growth and progression. Thus, the thioredoxin system has been proposed to be an attractive target for cancer therapy. This study gives the first comprehensive overview of the effects of TPCs on the transcriptome and proteome of glioblastoma cells. We reveal that under TPC treatment, mechanisms countersteering TrxR inhibition are activated in parallel to DNA-damage-responsive pathways. TPC pressure results in long-term compensatory upregulation of TrxR expression. In parallel, p53 is activated, leading to a range of regulations typical for cell-cycle-arrested cells such as upregulation of CDKN1A, induction of GADD45, inhibition of eIF5A maturation, and reduced phosphorylation of stathmin. We also show that TPCs induce endoplasmic reticulum stress, as they activate the unfolded protein response. This profiling study provides a thorough insight into the spectrum of cellular events resulting from specific TrxR inhibition and characterizes the TPC mode of action.
Authors:
Sasa Koncarevic; Sabine Urig; Klaus Steiner; Stefan Rahlfs; Christel Herold-Mende; Holger Sueltmann; Katja Becker
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-01-23
Journal Detail:
Title:  Free radical biology & medicine     Volume:  46     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-05-15     Completed Date:  2009-11-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1096-108     Citation Subset:  IM    
Affiliation:
Interdisciplinary Research Center, Justus-Liebig University, Giessen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle / drug effects
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  metabolism
DNA Damage
Gene Expression Profiling
Gene Expression Regulation / drug effects
Glioblastoma / drug therapy,  genetics*,  metabolism*,  pathology
Humans
Intercalating Agents / pharmacology*
Intracellular Signaling Peptides and Proteins / genetics,  metabolism
Oxidation-Reduction / drug effects
Peptide Initiation Factors / metabolism
Phenols / pharmacology*
Phosphorylation / drug effects
Protein Folding / drug effects
Proteome
Pyridines / pharmacology*
RNA-Binding Proteins / metabolism
Stathmin / metabolism
Sulfhydryl Compounds / pharmacology*
Thioredoxin-Disulfide Reductase / metabolism
Tumor Suppressor Protein p53 / genetics,  metabolism
Chemical
Reg. No./Substance:
0/4-mercaptophenol; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/GADD45 protein; 0/Intercalating Agents; 0/Intracellular Signaling Peptides and Proteins; 0/Peptide Initiation Factors; 0/Phenols; 0/Proteome; 0/Pyridines; 0/RNA-Binding Proteins; 0/Stathmin; 0/Sulfhydryl Compounds; 0/Tumor Suppressor Protein p53; 0/eukaryotic translation initiation factor 5A; 2637-34-5/2-thiopyridine; EC 1.8.1.9/Thioredoxin-Disulfide Reductase

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


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