TNF-induced modulations of phospholipid metabolism in human breast cancer cells

Liora Bogin , Moshe Z. Papa , Sylvie Polak-Charcon , Hadassa Degani
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引用次数: 47

Abstract

Tumor necrosis factor α (TNF) is a cytokine that is cytocidal for certain tumor cells and induces necrotic and apoptotic forms of cell death. Flow cytometry and transmission electron microscopy analysis demonstrated that in human breast cancer cells (MCF7) TNF induces cell cycle arrest in G0+G1/S, accompanied by apoptosis. 31P and 13C NMR spectroscopy was applied to study cellular metabolism of MCF7 cells during TNF-induced signal to apoptosis. Deuterated choline and 2H NMR spectroscopy were utilized to monitor the kinetics of the rate limiting reactions in phosphocholine metabolism. The NMR measurements revealed that immediately after administration of TNF, choline transport was inhibited by 52±6%. Later (∼15 h), the activity of phosphocholine:cytidine triphosphate cytidylyltransferase, a key enzyme in the biosynthesis of phosphatidylcholine, was enhanced two-fold. These two opposing changes led to a decrease in the level of phosphocholine. Throughout these changes the energetic state of the cells, determined by the level of nucleoside triphosphates and the rate of glucose metabolism via glycolysis, remained constant. The results indicate that TNF specifically modulates the kinetics of membrane-bound enzymes of the rate determining steps in phosphatidylcholine biosynthesis, possibly as part of early events involved in apoptosis.

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tnf诱导的人乳腺癌细胞磷脂代谢的调节
肿瘤坏死因子α (TNF)是一种细胞因子,对某些肿瘤细胞具有杀伤作用,可诱导坏死和凋亡形式的细胞死亡。流式细胞术和透射电镜分析表明,在人乳腺癌细胞(MCF7)中,TNF诱导细胞周期阻滞在G0+G1/S,并伴有凋亡。应用核磁共振31P和13C谱研究tnf诱导信号凋亡过程中MCF7细胞的细胞代谢。利用氘化胆碱和2H核磁共振光谱对磷胆碱代谢中的限速反应动力学进行了监测。核磁共振测量显示,在给药TNF后,胆碱转运被抑制了52±6%。随后(~ 15 h),磷脂酰胆碱生物合成的关键酶——磷脂酰胆碱三磷酸胞基转移酶(cytidine triphosphate cytidyylltransferase)的活性提高了两倍。这两种相反的变化导致了磷胆碱水平的下降。在这些变化中,由三磷酸核苷水平和糖酵解葡萄糖代谢速率决定的细胞能量状态保持不变。结果表明,TNF特异性调节磷脂酰胆碱生物合成速率决定步骤的膜结合酶的动力学,可能是凋亡早期事件的一部分。
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