Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition.
Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition.
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DOI：
10.1042/bj20120294
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发表时间：
2012-06-15
期刊：
影响因子：
--
通讯作者：
Hogg N
中科院分区：
文献类型：
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作者：
Diers AR;Broniowska KA;Chang CF;Hogg N
最近的研究强调了这样一个事实，即癌细胞具有改变的代谢表型，并且这种代谢重编程是驱动快速复制和增殖所必需的生物合成途径所必需的。具体地，最近已经认识到三羧酸（TCA）循环产生的中间体在调节癌细胞增殖中的重要性。单羧酸转运蛋白（MCT）的一个功能是转运TCA循环底物丙酮酸穿过质膜并进入线粒体，并且已经提出抑制MCT作为靶向癌症代谢途径的治疗策略。在这里，我们研究了不同的代谢底物（葡萄糖和丙酮酸）对乳腺癌细胞线粒体功能和增殖的影响。我们证明，与乳酸相比，在外源性丙酮酸存在下，癌细胞增殖更快。丙酮酸补充燃料线粒体耗氧量和储备呼吸能力，这种线粒体功能的增加与增殖潜力。此外，使用MCT抑制剂α-氰基-4-羟基肉桂酸抑制细胞丙酮酸摄取会损害线粒体呼吸并降低细胞生长。这些数据证明了线粒体代谢在增殖反应中的重要性，并强调了MCT抑制剂通过抑制腺苷酸激发的线粒体呼吸的新型作用机制。
Recent studies have highlighted the fact that cancer cells have an altered metabolic phenotype, and this metabolic reprogramming is required to drive biosynthesis pathways necessary for rapid replication and proliferation. Specifically, the importance of tricarboxylic acid (TCA) cycle-generated intermediates in the regulation of cancer cells proliferation has been recently appreciated. One function of monocarboxylate transporters (MCTs) is to transport the TCA cycle substrate pyruvate across the plasma membrane and into mitochondria, and inhibition of MCTs has been proposed as a therapeutic strategy to target metabolic pathways in cancer. Here, we examined the effect of different metabolic substrates (glucose and pyruvate) on mitochondrial function and proliferation in breast cancer cells. We demonstrated that cancer cells proliferate more rapidly in the presence of exogenous pyruvate when compared to lactate. Pyruvate supplementation fueled mitochondrial oxygen consumption and the reserve respiratory capacity, and this increase in mitochondrial function correlated with proliferative potential. In addition, inhibition of cellular pyruvate uptake using the MCT inhibitor α-cyano-4-hydroxycinnamic acid impaired mitochondrial respiration and decreased cell growth. These data demonstrate the importance of mitochondrial metabolism in proliferative responses and highlight a novel mechanism of action for MCT inhibitors through suppression of pyruvate-fueled mitochondrial respiration.