CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors
CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors
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DOI：
10.1073/pnas.1106123108
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发表时间：
2011-10-04
影响因子：
11.1
通讯作者：
Pouyssegur, Jacques
中科院分区：
文献类型：
--
作者：
Le Floch, Renaud;Chiche, Johanna;Pouyssegur, Jacques
恶性肿瘤表现出对糖酵解的依赖性增加，导致大量的乳酸输出，这是肿瘤发生的一个假设的关键步骤。乳酸主要由两个H+/乳酸协同转运蛋白MCT 1/MCT 4转运，其功能需要辅助蛋白CD 147/Basigin。首先，我们发现用AR-C155858阻断Ras转化的成纤维细胞中的MCT 1/2抑制了乳酸输出、糖酵解和肿瘤生长，而这些细胞中的MCT 4异位表达赋予了对MCT 1/2抑制的抗性并重建了致瘤性。一种缺乏呼吸作用（res（-））并完全依赖糖酵解提供能量的muerase衍生物显示出低致瘤性。这些res（-）细胞可以对MCT 1/2抑制产生抗性，并通过重新激活其内源性mct 4基因而变得高度致瘤性，突出显示了MCT 4（缺氧诱导型和肿瘤相关的乳酸/H+同向转运体）驱动致瘤性。第二，在人结肠腺癌细胞系（LS 174 T）中，我们发现通过诱导型shRNA联合沉默MCT 1/MCT 4，或单独沉默CD 147/Basigin，可显著降低糖酵解通量和肿瘤生长。然而，这两种沉默方法，减少肿瘤生长，显示出低水平的CD 147/Basigin，一种多功能的促肿瘤蛋白。为了深入了解CD 147/Basigin功能，我们设计了实验，通过锌指核酸酶介导的mct 4和basigin敲除，将MCT与Basigin表达解偶联。在无MCT 4的Basigin（高）细胞中抑制MCT 1可抑制肿瘤生长。相反，在保持MCT活性的Basigin无效细胞中，致瘤性不受影响。总的来说，这些发现强调了CD 147/Basigin的主要促肿瘤作用是通过MCT 1/MCT 4活性控制糖酵解肿瘤的能量学，并且阻断乳酸输出提供了有效的抗癌策略。
Malignant tumors exhibit increased dependence on glycolysis, resulting in abundant export of lactic acid, a hypothesized key step in tumorigenesis. Lactic acid is mainly transported by two H+/lactate symporters, MCT1/MCT4, that require the ancillary protein CD147/Basigin for their functionality. First, we showed that blocking MCT1/2 in Ras-transformed fibroblasts with AR-C155858 suppressed lactate export, glycolysis, and tumor growth, whereas ectopic expression of MCT4 in these cells conferred resistance to MCT1/2 inhibition and reestablished tumorigenicty. A mutant-derivative, deficient in respiration (res(-)) and exclusively relying on glycolysis for energy, displayed low tumorigenicity. These res(-) cells could develop resistance to MCT1/2 inhibition and became highly tumorigenic by reactivating their endogenous mct4 gene, high-lighting that MCT4, the hypoxia-inducible and tumor-associated lactate/H+ symporter, drives tumorigenicity. Second, in the human colon adenocarcinoma cell line (LS174T), we showed that combined silencing of MCT1/MCT4 via inducible shRNA, or silencing of CD147/Basigin alone, significantly reduced glycolytic flux and tumor growth. However, both silencing approaches, which reduced tumor growth, displayed a low level of CD147/Basigin, a multifunctional protumoral protein. To gain insight into CD147/Basigin function, we designed experiments, via zinc finger nuclease-mediated mct4 and basigin knockouts, to uncouple MCTs from Basigin expression. Inhibition of MCT1 in MCT4-null, Basigin(high) cells suppressed tumor growth. Conversely, in Basigin-null cells, in which MCT activity had been maintained, tumorigenicity was not affected. Collectively, these findings highlight that the major protumoral action of CD147/Basigin is to control the energetics of glycolytic tumors via MCT1/MCT4 activity and that blocking lactic acid export provides an efficient anticancer strategy.