ATP citrate lyase inhibition can suppress tumor cell growth
ATP citrate lyase inhibition can suppress tumor cell growth
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DOI：
10.1016/j.ccr.2005.09.008
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发表时间：
2005-10-01
期刊：
影响因子：
50.3
通讯作者：
Thompson, CB
中科院分区：
文献类型：
--
作者：
Hatzivassiliou, G;Zhao, FP;Thompson, CB
18-F-2-脱氧葡萄糖PET显像证实，许多肿瘤显示高葡萄糖利用率。以超过生物能量需求的速率通过糖酵解分解代谢葡萄糖的一个潜在优点是生长的细胞可以将过量的糖酵解终产物丙酮酸盐重定向至脂质合成。这种从头脂质合成对于膜产生和蛋白质的基于脂质的翻译后修饰是必需的。连接葡萄糖代谢与脂质合成的关键酶是ATP柠檬酸裂解酶（ACL），其催化柠檬酸盐转化为细胞溶质乙酰辅酶A。通过RNAi或化学抑制剂SB-204990的ACL抑制限制了显示有氧糖酵解的肿瘤细胞的体外增殖和存活。相同的治疗还减少体内肿瘤生长并诱导分化。
Many tumors display a high rate of glucose utilization, as evidenced by 18-F-2-deoxyglucose PET imaging. One potential advantage of catabolizing glucose through glycolysis at a rate that exceeds bioenergetic need is that the growing cell can redirect the excess glycolytic end product pyruvate toward lipid synthesis. Such de novo lipid synthesis is necessary for membrane production and lipid-based posttranslational modification of proteins. A key enzyme linking glucose metabolism to lipid synthesis is ATP citrate lyase (ACL), which catalyzes the conversion of citrate to cytosolic acetyl-CoA. ACL inhibition by RNAi or the chemical inhibitor SB-204990 limits in vitro proliferation and survival of tumor cells displaying aerobic glycolysis. The same treatments also reduce in vivo tumor growth and induce differentiation.