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First published on November 25, 2008
This version was published on January 1, 2009
Neuro Oncol 2009 11(4):368-380; DOI:10.1215/15228517-2008-106
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Duke University Press

Basic and Translational Investigations

Lactate promotes glioma migration by TGF-β2–dependent regulation of matrix metalloproteinase-2

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 and Peter Hau

Department of Neurology (F.B., P.L., A.D., C.P.B., T.N.-J., U.B., P.H.), Institute of Functional Genomics (K.D., P.J.O.), Department of Hematology and Oncology (M.Ka., M.Kr.), and Institute of Pathology (A.-K.B.), University of Regensburg, Regensburg, Germany; Neurology Research Centre, Royal Brisbane and Women's Hospital, Queensland, Australia (F.B.); Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany (T.N.-J.)

Address correspondence to Peter Hau, Department of Neurology, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany (peter.hau{at}medbo.de).

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-β2 (TGF-β2) 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-β2–mediated migration of glioma cells. Small interfering RNA directed against LDH-A (siLDH-A) suppresses, and lactate induces, TGF-β2 expression, suggesting that lactate metabolism is strongly associated with TGF-β2 in glioma cells. Here we demonstrate that TGF-β2 enhances expression, secretion, and activation of matrix metalloproteinase-2 (MMP-2) and induces the cell surface expression of integrin {alpha}vβ3 receptors. In spheroid and Boyden chamber migration assays, inhibition of MMP-2 activity using a specific MMP-2 inhibitor and blocking of integrin {alpha}vβ3 abrogated glioma cell migration stimulated by TGF-β2. Furthermore, siLDH-A inhibited MMP2 activity, leading to inhibition of glioma migration. Taken together, we define an LDH-A–induced and TGF-β2–coordinated regulatory cascade of transcriptional regulation of MMP-2 and integrin {alpha}vβ3. This novel interaction between lactate metabolism and TGF-β2 might constitute a crucial mechanism for glioma migration.

Key Words: glioma • lactate • LDH-A • MMP-2 • TGF-β2


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