Lactate promotes glioma migration by TGF-beta2-dependent regulation of matrix metalloproteinase-2.

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.

• Authors: 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
• Journal: Neuro-oncology (Neuro Oncol) Vol. 11 Issue 4 Pg. 368-80 (Aug 2009) ISSN: 1522-8517 [Print] England
• PMID: 19033423 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Integrin alphaVbeta3
• Isoenzymes
• Matrix Metalloproteinase Inhibitors
• RNA, Messenger
• RNA, Small Interfering
• TGFB2 protein, human
• Transforming Growth Factor beta2
• L-Lactate Dehydrogenase
• Lactate Dehydrogenase 5
• Matrix Metalloproteinase 2
• Glucose

Topics

• Brain Neoplasms (metabolism, pathology)
• Cell Movement
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Gene Expression Regulation, Neoplastic
• Glioma (metabolism, pathology)
• Glucose (analysis)
• Humans
• Integrin alphaVbeta3 (antagonists & inhibitors, metabolism)
• Isoenzymes (physiology)
• L-Lactate Dehydrogenase (physiology)
• Lactate Dehydrogenase 5
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase Inhibitors
• 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