Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis.
Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis.
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DOI：
10.1158/0008-5472.can-13-2034
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发表时间：
2014-02-01
期刊：
影响因子：
11.2
通讯作者：
Cleveland JL
中科院分区：
文献类型：
--
作者：
Doherty JR;Yang C;Scott KE;Cameron MD;Fallahi M;Li W;Hall MA;Amelio AL;Mishra JK;Li F;Tortosa M;Genau HM;Rounbehler RJ;Lu Y;Dang CV;Kumar KG;Butler AA;Bannister TD;Hooper AT;Unsal-Kacmaz K;Roush WR;Cleveland JL
MYC癌蛋白诱导驱动有氧糖酵解的基因，包括产生乳酸的乳酸脱氢酶-A。在这里，我们报道Myc控制乳酸转运蛋白SLC16A1/MCT1的转录，并且MCT1水平的升高在癌前和肿瘤性Eμ-Myc转基因B细胞以及有MYC或MYCN参与的人类恶性肿瘤中明显存在。值得注意的是，破坏MCT1功能会导致细胞内乳酸积累，从而迅速阻止肿瘤细胞生长和糖酵解，导致糖酵解中间产物显著改变，葡萄糖转运减少，以及ATP、NADPH和谷胱甘肽水平下降。谷胱甘肽的减少会导致过氧化氢增加，线粒体受损，最终导致细胞死亡。最后，二甲双胍强制糖酵解治疗增强了这种反应和MCT1抑制剂的疗效，这表明MYC/MCT1表达的恶性肿瘤是一种有吸引力的联合治疗方法。
Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1, and that elevated MCT1 levels are manifest in premalignant and neoplastic Eμ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, and reductions in glucose transport, and in levels of ATP, NADPH and glutathione. Reductions in glutathione then lead to increases in hydrogen peroxide, mitochondrial damage and, ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies.