Baumann, Fusun, Leukel, Petra, Doerfelt, Anett, Beier, Christoph P., Dettmer, Katja, Oefner, Peter J., Kastenberger, Michael, Kreutz, Marina, Nickl-Jockschat, Thomas, Bogdahn, Ulrich, Bosserhoff, Anja-Katrin and Hau, Peter
(2009)
Lactate promotes glioma migration by TGF-beta2-dependent regulation of matrix metalloproteinase-2.
Neuro-oncology 11 (4), pp. 368-380.
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Abstract
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 ...
Abstract
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.
Export bibliographical data
| Item type: | Article |
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| Date: | 2009 |
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| Institutions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner)
Medicine > Zentren des Universitätsklinikums Regensburg > Zentrum für Hirntumore (ZHT) |
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| Identification Number: | | Value | Type |
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| 18510920 | PubMed ID | | 10.1215/15228517-2008-106 | DOI |
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| Classification: | | Notation | Type |
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| Brain Neoplasms/pathology | MESH | | Cell Movement | MESH | | Enzyme-Linked Immunosorbent Assay | MESH | | Flow Cytometry | MESH | | Gene Expression Regulation, Neoplastic | MESH | | Glioma/pathology | MESH | | Glucose/analysis | MESH | | Humans | MESH | | Integrin alphaVbeta3/metabolism | MESH | | Isoenzymes/physiology | MESH | | L-Lactate Dehydrogenase/physiology | MESH | | Matrix Metalloproteinase 2/metabolism | MESH | | Matrix Metalloproteinase Inhibitors | MESH | | RNA, Messenger/metabolism | MESH | | RNA, Small Interfering/pharmacology | MESH | | Reverse Transcriptase Polymerase Chain Reaction | MESH | | Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization | MESH | | Transforming Growth Factor beta2/metabolism | MESH | | Tumor Cells, Cultured | MESH |
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| Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine |
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| Status: | Published |
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| Refereed: | Yes, this version has been refereed |
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| Created at the University of Regensburg: | Unknown |
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| Item ID: | 29313 |
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