Lactate promotes glioma migration by TGF-β2–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.

Pyruvate kinase type M2 is upregulated in colorectal cancer and promotes proliferation and migration of colon cancer cells

“…Although the molecular mechanisms are not clearly understood, lactate has been found to increase migration of various cancer cell lines (37,41). Recent data indicated that transforming growth factor beta (TGF-b) signaling pathway might be a mediator of the lactateassociated effects on migration of cancer cells (42). Moreover, lactate stimulates some cytokines, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), resulting lactate-induced angiogenesis and increased tumor metastasis (43,44).…”

The acidic microenvironment as a possible niche of dormant tumor cells

“…Lactic acid was shown to induce both transcription and protein secretion of TGFβ2 in glioma cells [32] and to induce TGFβ1 production in in vivo model [33]. More recently, we found that an acidic microenvironment is able to promote TGFβ secretion and signaling in mesenchymal stem cells (MSC), driving the progression to malignancy in a melanoma cell system [34] and suggesting that acidity is a strong inducer of TGFβ family members.…”

Cancer metabolism in space and time: Beyond the Warburg effect

“…Sev eral other metabo lites were also shown to in duce EMT. For in stance, lac tic acid was iden ti fied to be an ac ti va tor of TGF β2 path way in a glioma cell line [225]. More over, can cer cells un der go ing EMT ac cu mu late fatty acids that are taken up via CD36, in turn stim u lat ing Wnt and TGF β path ways [197].…”