Document Detail

Lactate promotes glioma migration by TGF-beta2-dependent regulation of matrix metalloproteinase-2.
MedLine Citation:
PMID:  19033423     Owner:  NLM     Status:  MEDLINE    
Lactate dehydrogenase type A (LDH-A) is a key metabolic enzyme catalyzing pyruvate into lactate and is excessively expressed by tumor cells. Transforming growth factor-beta2 (TGF-beta2) is a key regulator of invasion in high-grade gliomas, partially by inducing a mesenchymal phenotype and by remodeling the extracellular matrix. In this study, we tested the hypothesis that lactate metabolism regulates TGF-beta2-mediated migration of glioma cells. Small interfering RNA directed against LDH-A (siLDH-A) suppresses, and lactate induces, TGF-beta2 expression, suggesting that lactate metabolism is strongly associated with TGF-beta2 in glioma cells. Here we demonstrate that TGF-beta2 enhances expression, secretion, and activation of matrix metalloproteinase-2 (MMP-2) and induces the cell surface expression of integrin alpha(v)beta(3) receptors. In spheroid and Boyden chamber migration assays, inhibition of MMP-2 activity using a specific MMP-2 inhibitor and blocking of integrin alpha(v)beta(3) abrogated glioma cell migration stimulated by TGF-beta2. Furthermore, siLDH-A inhibited MMP2 activity, leading to inhibition of glioma migration. Taken together, we define an LDH-A-induced and TGF-beta2-coordinated regulatory cascade of transcriptional regulation of MMP-2 and integrin alpha(v)beta(3). This novel interaction between lactate metabolism and TGF-beta2 might constitute a crucial mechanism for glioma migration.
Fusun Baumann; Petra Leukel; Anett Doerfelt; Christoph P Beier; Katja Dettmer; Peter J Oefner; Michael Kastenberger; Marina Kreutz; Thomas Nickl-Jockschat; Ulrich Bogdahn; Anja-Katrin Bosserhoff; Peter Hau
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-25
Journal Detail:
Title:  Neuro-oncology     Volume:  11     ISSN:  1522-8517     ISO Abbreviation:  Neuro-oncology     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-08-07     Completed Date:  2009-09-10     Revised Date:  2010-09-23    
Medline Journal Info:
Nlm Unique ID:  100887420     Medline TA:  Neuro Oncol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  368-80     Citation Subset:  IM    
Department of Neurology, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany.
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MeSH Terms
Brain Neoplasms / metabolism,  pathology*
Cell Movement*
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Gene Expression Regulation, Neoplastic
Glioma / metabolism,  pathology*
Glucose / analysis
Integrin alphaVbeta3 / antagonists & inhibitors,  metabolism*
Isoenzymes / physiology
L-Lactate Dehydrogenase / physiology*
Matrix Metalloproteinase 2 / antagonists & inhibitors,  metabolism*
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Transforming Growth Factor beta2 / metabolism*
Tumor Cells, Cultured
Reg. No./Substance:
0/Integrin alphaVbeta3; 0/Isoenzymes; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/TGFB2 protein, human; 0/Transforming Growth Factor beta2; 50-99-7/Glucose; EC Dehydrogenase; EC dehydrogenase 5; EC Metalloproteinase 2

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