© Copyright 2008 by the Society for Neuro-Oncology
Received August 6, 2008
Accepted November 11, 2008
Basic and Translational Investigations
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Lactate promotes glioma migration by TGF-beta2 dependent regulation of matrix metalloproteinase-2
Peter Hau 1*,
Fusun Baumann 2,
Petra Leukel 3,
Anett Doerfelt 3,
Christoph P. Beier 3,
Katja Dettmer 4,
Peter J. Oefner 4,
Michael Kastenberger 5,
Marina Kreutz 5,
Thomas Nickl-Jockschat 6,
Ulrich Bogdahn 3,
Anja-Katrin Bosserhoff 7
1 Department of Neurology, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany
2 Department of Neurology, University of Regensburg, Regensburg, Germany; Neurology Research Centre, Royal Brisbane and Women's Hospital, Queensland, Australia
3 Department of Neurology, University of Regensburg, Regensburg, Germany
4 Institute of Functional Genomics, University of Regensburg, Regensburg, Germany
5 Department of Hematology and Oncology, University of Regensburg, Regensburg, Germany
6 Department of Neurology, University of Regensburg, Regensburg, Germany; Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany
7 Institute of Pathology, University of Regensburg, Regensburg, Germany
* To whom correspondence should be addressed. E-mail: peter.hau{at}medbo.de.
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Abstract |
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Lactate dehydrogenase type A (LDH-A) is a metabolic key 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. We demonstrate that TGF-beta2 enhances expression, secretion and activation of MMP-2 and induces the cell surface expression of integrin alphavbeta3 receptors. In spheroid and Boyden chamber migration assays, inhibition of MMP-2 activity using a specific MMP-2 inhibitor and blocking of integrin alphavbeta3 abrogated glioma cell-migration stimulated by TGF-beta2. Furthermore, siLDH-A inhibited MMP2 activity leading to inhibition of glioma migration. Taken together, we define a LDH-A induced and TGF-beta2 coordinated regulatory cascade of transcriptional regulation of MMP-2 and integrin alphavbeta3. This novel interaction between lactate metabolism and TGF-beta2 might constitute a crucial mechanism for glioma migration.
Key Words:
glioma, lactate, LDH-A, MMP-2, TGF-beta2
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