PHLPP regulates hexokinase 2-dependent glucose metabolism in colon cancer cells.
PHLPP regulates hexokinase 2-dependent glucose metabolism in colon cancer cells.
复制标题
PHLPP调节结肠癌细胞中的己糖酶2依赖性葡萄糖代谢。
DOI：
10.1038/cddiscovery.2016.103
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发表时间：
2017
影响因子：
7
通讯作者：
Gao T
中科院分区：
文献类型：
--
作者：
Xiong X;Wen YA;Mitov MI;C Oaks M;Miyamoto S;Gao T
葡萄糖代谢增强被认为是癌细胞为了产生能量而适应的最重要的代谢变化之一，以及支持快速增殖的高水平糖酵解中间产物。富含亮氨酸的重复蛋白磷酸酶(PHLPP)是一类新的丝氨酸/苏氨酸蛋白磷酸酶家族，在多种类型的人类癌症中发挥肿瘤抑制作用。在这里，我们确定了PHLPP在调节结肠癌细胞葡萄糖代谢中的作用。PHLPP基因敲除后，葡萄糖消耗率和乳酸产量增加，而PHLPP基因过表达则相反。利用海马氏细胞外通量分析仪进行的生物能量分析显示，沉默PHLPP表达诱导了结肠癌细胞的糖酵解转变。在机制上，我们发现PHLPP与Akt和己糖激酶2(HK2)在结肠癌细胞线粒体部分形成了复合体，并且PHLPP的敲除增强了Akt介导的HK2的磷酸化和线粒体定位。减少HK2的表达或用Akt和HK2抑制剂处理细胞可逆转PHLPP丢失诱导的糖酵解增加。此外，PHLPP基因敲除细胞对葡萄糖作为主要能源上瘾，因为葡萄糖饥饿显著降低了癌细胞的存活率。由于HK2是决定葡萄糖通量方向和大小的关键酶，我们的研究确定PHLPP是一种通过控制HK2活性来调节结肠癌细胞中葡萄糖代谢的新的调节因子。
Increased glucose metabolism is considered as one of the most important metabolic alterations adapted by cancer cells in order to generate energy as well as high levels of glycolytic intermediates to support rapid proliferation. PH domain leucine-rich repeat protein phosphatase (PHLPP) belongs to a novel family of Ser/Thr protein phosphatases that function as tumor suppressors in various types of human cancer. Here we determined the role of PHLPP in regulating glucose metabolism in colon cancer cells. Knockdown of PHLPP increased the rate of glucose consumption and lactate production, whereas overexpression of PHLPP had the opposite effect. Bioenergetic analysis using Seahorse Extracelluar Flux Analyzer revealed that silencing PHLPP expression induced a glycolytic shift in colon cancer cells. Mechanistically, we found that PHLPP formed a complex with Akt and hexokinase 2 (HK2) in the mitochondrial fraction of colon cancer cells and knockdown of PHLPP enhanced Akt-mediated phosphorylation and mitochondrial localization of HK2. Depletion of HK2 expression or treating cells with Akt and HK2 inhibitors reversed PHLPP loss-induced increase in glycolysis. Furthermore, PHLPP knockdown cells became addicted to glucose as a major energy source in that glucose starvation significantly decreased cancer cell survival. As HK2 is the key enzyme that determines the direction and magnitude of glucose flux, our study identified PHLPP as a novel regulator of glucose metabolism by controlling HK2 activity in colon cancer cells.