Lactate promotes glioma migration by TGF-β2-dependent regulation of matrix metalloproteinase-2
Lactate promotes glioma migration by TGF-β2-dependent regulation of matrix metalloproteinase-2
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DOI：
10.1215/15228517-2008-106
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发表时间：
2009-08-01
期刊：
影响因子：
15.9
通讯作者：
Hau, Peter
中科院分区：
文献类型：
--
作者：
Baumann, Fusun;Leukel, Petra;Hau, Peter
乳酸脱氢酶A（LDH-A）是催化丙酮酸转化为乳酸的关键代谢酶，在肿瘤细胞中过度表达。转化生长因子-β 2（TGF-β 2）是高级别胶质瘤侵袭的关键调节因子，部分通过诱导间充质表型和重塑细胞外基质。在这项研究中，我们测试了乳酸代谢调节TGF-β 2介导的胶质瘤细胞迁移的假设。针对LDH-A的小干扰RNA（siLDHA）抑制和乳酸诱导TGF-β 2表达，表明胶质瘤细胞中乳酸代谢与TGF-β 2密切相关。在这里，我们证明了TGF-β 2增强基质金属蛋白酶-2（MMP-2）的表达、分泌和活化，并诱导整合素α（v）β（3）受体的细胞表面表达。在球状体和Boyden室迁移试验中，使用特异性MMP-2抑制剂抑制MMP-2活性和阻断整合素avb3消除了TGF-β 2刺激的胶质瘤细胞迁移。此外，siLDH-A抑制MMP 2活性，导致胶质瘤迁移的抑制。综上所述，我们确定了MMP-2和整合素α（v）β（3）转录调控的LDH-A诱导和TGF-β 2协调的调控级联。乳酸代谢和TGF-β 2之间的这种新的相互作用可能构成胶质瘤迁移的重要机制。Neuro-Oncology 11，368 - 380，2009（Posted to Neuro-Oncology [serial online]，Doc. D08 - 00206，2008年11月25日。网址www.example.com; DOI：10.1215/15228517 - 2008 - 106）
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)