Lactate promotes glioma migration by TGF-beta2-dependent regulation of matrix metalloproteinase-2.
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.
Baumann
Fusun
F
Department of Neurology, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany.
Leukel
Petra
P
Doerfelt
Anett
A
Beier
Christoph P
CP
Dettmer
Katja
K
Oefner
Peter J
PJ
Kastenberger
Michael
M
Kreutz
Marina
M
Nickl-Jockschat
Thomas
T
Bogdahn
Ulrich
U
Bosserhoff
Anja-Katrin
AK
Hau
Peter
P
D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D005947:Glucose / Q000032:analysis; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007527:Isoenzymes / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000502:physiology*; D000080864:Lactate Dehydrogenase 5; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D039302:Integrin alphaVbeta3; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D020778:Matrix Metalloproteinase 2; D005947:Glucose