Bauer Daniel E, Hatzivassiliou Georgia, Zhao Fangping, Andreadis Charalambos, Thompson Craig B
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Oncogene. 2005 Sep 15;24(41):6314-22. doi: 10.1038/sj.onc.1208773.
Cell proliferation requires a constant supply of lipids and lipid precursors to fuel membrane biogenesis and protein modification. Cytokine stimulation of hematopoietic cells directly stimulates glucose utilization in excess of bioenergetic demand, resulting in a shift from oxidative to glycolytic metabolism. A potential benefit of this form of metabolism is the channeling of glucose into biosynthetic pathways. Here we report that glucose supports de novo lipid synthesis in growing hematopoietic cells in a manner regulated by cytokine availability and the PI 3 K/Akt signaling pathway. The net conversion of glucose to lipid is dependent on the ability of cells to produce cytosolic acetyl CoA from mitochondria-derived citrate through the action of ATP citrate lyase (ACL). Stable knockdown of ACL leads to a significant impairment of glucose-dependent lipid synthesis and an elevation of mitochondrial membrane potential. Cells with ACL knockdown display decreased cytokine-stimulated cell proliferation. In contrast, these cells resist cell death induced by either cytokine or glucose withdrawal. However, ACL knockdown significantly impairs Akt-mediated tumorigenesis in vivo. These data suggest that enzymes involved in the conversion of glucose to lipid may be targets for the treatment of pathologic cell growth.
细胞增殖需要持续供应脂质和脂质前体，以为膜生物合成和蛋白质修饰提供能量。造血细胞的细胞因子刺激直接刺激葡萄糖的利用，使其超过生物能量需求，导致代谢从氧化代谢转变为糖酵解代谢。这种代谢形式的一个潜在益处是将葡萄糖导向生物合成途径。在此我们报告，葡萄糖以一种受细胞因子可用性和PI 3 K/Akt信号通路调控的方式，支持正在生长的造血细胞从头合成脂质。葡萄糖向脂质的净转化取决于细胞通过ATP柠檬酸裂解酶（ACL）的作用，从线粒体衍生的柠檬酸产生胞质乙酰辅酶A的能力。ACL的稳定敲低导致葡萄糖依赖性脂质合成显著受损，线粒体膜电位升高。ACL敲低的细胞显示细胞因子刺激的细胞增殖减少。相反，这些细胞抵抗由细胞因子或葡萄糖剥夺诱导的细胞死亡。然而，ACL敲低在体内显著损害Akt介导的肿瘤发生。这些数据表明，参与葡萄糖向脂质转化的酶可能是治疗病理性细胞生长的靶点。
