Metabolic changes in cancer cells upon suppression of MYC.
Metabolic changes in cancer cells upon suppression of MYC.
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DOI：
10.1186/2049-3002-1-7
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发表时间：
2013-02-04
影响因子：
5.9
通讯作者：
Chandel NS
中科院分区：
文献类型：
--
作者：
Anso E;Mullen AR;Felsher DW;Matés JM;Deberardinis RJ;Chandel NS
癌细胞参与有氧糖酵解和氨解，部分通过激活MYC来满足其生物合成和能量需求。先前的报道已经表征了MYC功能丧失或获得后增殖细胞中的代谢变化。然而，MYC依赖性癌细胞和它们的同基因分化对应物之间的代谢差异尚未在体外MYC抑制后表征。在这里，我们报告MYC依赖性小鼠成骨肉瘤和分化的类骨细胞诱导后MYC抑制代谢的变化。虽然成骨肉瘤细胞在MYC抑制后增加了耗氧量和备用呼吸能力，但它们在葡萄糖和谷氨酰胺消耗以及它们各自对柠檬酸盐池的贡献方面显示出最小的变化。然而，谷氨酰胺显着诱导耗氧MYC的存在下，这是依赖于转氨酶。此外，抑制氨基转移酶选择性地减少细胞增殖和生存的成骨肉瘤MYC表达细胞。在骨样细胞和成骨肉瘤细胞之间，活性氧水平和细胞死亡对活性氧诱导剂的敏感性变化很小。尽管如此，靶向骨髓的抗氧化剂Mito-维生素E仍然减少了MYC依赖性成骨肉瘤细胞的增殖。这些数据突出表明，转氨酶和线粒体ROS可能是MYC驱动的肿瘤中癌症治疗的有吸引力的靶点。
Cancer cells engage in aerobic glycolysis and glutaminolysis to fulfill their biosynthetic and energetic demands in part by activating MYC. Previous reports have characterized metabolic changes in proliferating cells upon MYC loss or gain of function. However, metabolic differences between MYC-dependent cancer cells and their isogenic differentiated counterparts have not been characterized upon MYC suppression in vitro. Here we report metabolic changes between MYC-dependent mouse osteogenic sarcomas and differentiated osteoid cells induced upon MYC suppression. While osteogenic sarcoma cells increased oxygen consumption and spare respiratory capacity upon MYC suppression, they displayed minimal changes in glucose and glutamine consumption as well as their respective contribution to the citrate pool. However, glutamine significantly induced oxygen consumption in the presence of MYC which was dependent on aminotransferases. Furthermore, inhibition of aminotransferases selectively diminished cell proliferation and survival of osteogenic sarcoma MYC-expressing cells. There were minimal changes in ROS levels and cell death sensitivity to reactive oxygen species (ROS)-inducing agents between osteoid cells and osteogenic sarcoma cells. Nevertheless, the mitochondrial-targeted antioxidant Mito-Vitamin E still diminished proliferation of MYC-dependent osteogenic sarcoma cells. These data highlight that aminotransferases and mitochondrial ROS might be attractive targets for cancer therapy in MYC-driven tumors.