Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice
Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice
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DOI：
10.1172/jci36843
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发表时间：
2008-12-01
影响因子：
15.9
通讯作者：
Dewhirst, Mark W.
中科院分区：
文献类型：
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作者：
Sonveaux, Pierre;Vegran, Frederique;Dewhirst, Mark W.
肿瘤含有含氧和缺氧区域，因此肿瘤细胞群是异质的。低血糖肿瘤细胞主要使用葡萄糖进行糖酵解能量产生并释放乳酸，产生反映肿瘤中氧梯度的乳酸梯度。相比之下，氧合肿瘤细胞被认为主要使用葡萄糖来产生氧化能量。虽然乳酸通常被认为是一种废物，但我们现在表明，它是一种重要的底物，为含氧肿瘤细胞的氧化代谢提供燃料。因此，存在一种共生关系，其中糖酵解和氧化肿瘤细胞相互调节它们获得能量代谢物的途径。我们确定了单羧酸转运蛋白I（MCTI）作为乳酸摄取的人宫颈鳞癌细胞罚款，优先利用乳酸的氧化代谢的主要途径。在这些细胞中用α-氰基-4-羟基肉桂酸（CHC）或siRNA抑制MCT 1诱导了从乳酸盐驱动的呼吸到糖酵解的转变。在给予CHC后，在肺癌小鼠模型和异种移植的人结直肠腺癌细胞中观察到由含氧肿瘤细胞从乳酸盐燃料的呼吸到糖酵解的类似转换。这延缓了肿瘤生长，因为缺氧/糖酵解肿瘤细胞死于葡萄糖饥饿，并使剩余的细胞对辐射敏感。由于发现MCT 1在一系列原发性人类肿瘤中表达，我们认为MCTI抑制具有临床抗肿瘤潜力。
Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter I (MCTI) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell fine that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with alpha-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCTI inhibition has clinical antitumor potential.