Lactate promotes glioma migration by TGF-β2-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-beta 2 (TGF-beta 2) 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-beta 2-mediated migration of glioma cells. Small interfering RNA directed against LDH-A (siLDHA) suppresses, and lactate induces, TGF-beta 2 expression, suggesting that lactate metabolism is strongly associated with TGF-beta 2 in glioma cells. Here we demonstrate that TGF-beta 2 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 avb3 abrogated glioma cell migration stimulated by TGF-beta 2. Furthermore, siLDH-A inhibited MMP2 activity, leading to inhibition of glioma migration. Taken together, we define an LDH-A-induced and TGF-beta 2-coordinated regulatory cascade of transcriptional regulation of MMP-2 and integrin alpha(v)beta(3). This novel interaction between lactate metabolism and TGF-beta 2 might constitute a crucial mechanism for glioma migration. Neuro-Oncology 11, 368-380, 2009 (Posted to Neuro-Oncology [serial online], Doc. D08-00206, November 25, 2008. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2008-106)