Document Detail


Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib.
MedLine Citation:
PMID:  19567817     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Targeting the ubiquitin-proteasome pathway with the proteasome inhibitor bortezomib has emerged as a promising approach for the treatment of several malignancies. The cellular and molecular effects of this agent on colorectal cancer cells are poorly characterized. This study investigated the antiproliferative effect of bortezomib on colorectal cancer cell lines (Caco-2 and HRT-18). In order to define the proteins potentially involved in the mechanisms of action, proteome profiling was applied to detect the proteins altered by bortezomib. The in vitro efficacy of bortezomib as a single agent in colorectal cancer cell lines was confirmed. Proteome profiling with two-dimensional PAGE followed by mass spectrometry revealed the up-regulation of the major inducible isoform of heat shock protein 70 (hsp72) and lactate dehydrogenase B in both cell lines, as well as the induction of aldo-keto reductase family 1 member B10 (AKR1B10) in HRT-18 cells. Both AKR1B10 and hsp72 exert cell-protective functions. This study shows for the first time a bortezomib-induced up-regulation of AKR1B10. Small interfering RNA-mediated inhibition of this enzyme with known intracellular detoxification function sensitized HRT-18 cells to therapy with the proteasome inhibitor. To further characterize the relevance of AKR1B10 for colorectal tumors, immunohistochemical expression was shown in 23.2% of 125 tumor specimens. These findings indicate that AKR1B10 might be a target for combination therapy with bortezomib.
Authors:
Judith Loeffler-Ragg; Doris Mueller; Gabriele Gamerith; Thomas Auer; Sergej Skvortsov; Bettina Sarg; Ira Skvortsova; Klaus J Schmitz; Hans-Jörg Martin; Jens Krugmann; Hakan Alakus; Edmund Maser; Jürgen Menzel; Wolfgang Hilbe; Herbert Lindner; Kurt W Schmid; Heinz Zwierzina
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-06-30
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  8     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-15     Completed Date:  2009-10-19     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1995-2006     Citation Subset:  IM    
Affiliation:
Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria. Judith.Loeffler@i-med.ac.at
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Reductase / biosynthesis*
Blotting, Western
Boronic Acids / pharmacology*
Cell Cycle / drug effects
Cohort Studies
Colorectal Neoplasms / drug therapy*,  metabolism
Cyclooxygenase 2 / metabolism
Electrophoresis, Gel, Two-Dimensional
HSP72 Heat-Shock Proteins / metabolism
Humans
Phosphorylation / drug effects
Protease Inhibitors / pharmacology*
Proteome / analysis*
Proto-Oncogene Proteins c-akt / metabolism
Pyrazines / pharmacology*
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Survival Rate
Tissue Array Analysis
Tumor Cells, Cultured
Tumor Markers, Biological / metabolism
Chemical
Reg. No./Substance:
0/Boronic Acids; 0/HSP72 Heat-Shock Proteins; 0/Protease Inhibitors; 0/Proteome; 0/Pyrazines; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Tumor Markers, Biological; 0/bortezomib; EC 1.1.1.-/AKR1B10 protein, human; EC 1.1.1.21/Aldehyde Reductase; EC 1.14.99.1/Cyclooxygenase 2; EC 2.7.11.1/Proto-Oncogene Proteins c-akt

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


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